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1
Doretto, Lucas B., Arno J. Butzge, Rafael T. Nakajima, Emanuel R. M. Martinez, Beatriz Marques de Souza, Maira da Silva Rodrigues, Ivana F. Rosa, et al. "Gdnf Acts as a Germ Cell-Derived Growth Factor and Regulates the Zebrafish Germ Stem Cell Niche in Autocrine- and Paracrine-Dependent Manners." Cells 11, no. 8 (April 11, 2022): 1295. http://dx.doi.org/10.3390/cells11081295.
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Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GDNF Family Receptor α1-GFRα1) are well known to mediate spermatogonial stem cell (SSC) proliferation and survival in mammalian testes. In nonmammalian species, Gdnf and Gfrα1 orthologs have been found but their functions remain poorly investigated in the testes. Considering this background, this study aimed to understand the roles of the Gdnf-Gfrα1 signaling pathway in zebrafish testes by combining in vivo, in silico and ex vivo approaches. Our analysis showed that zebrafish exhibit two paralogs for Gndf (gdnfa and gdnfb) and its receptor, Gfrα1 (gfrα1a and gfrα1b), in accordance with a teleost-specific third round of whole genome duplication. Expression analysis further revealed that both ligands and receptors were expressed in zebrafish adult testes. Subsequently, we demonstrated that gdnfa is expressed in the germ cells, while Gfrα1a/Gfrα1b was detected in early spermatogonia (mainly in types Aund and Adiff) and Sertoli cells. Functional ex vivo analysis showed that Gdnf promoted the creation of new available niches by stimulating the proliferation of both type Aund spermatogonia and their surrounding Sertoli cells but without changing pou5f3 mRNA levels. Strikingly, Gdnf also inhibited late spermatogonial differentiation, as shown by the decrease in type B spermatogonia and down-regulation of dazl in a co-treatment with Fsh. Altogether, our data revealed that a germ cell-derived factor is involved in maintaining germ cell stemness through the creation of new available niches, supporting the development of spermatogonial cysts and inhibiting late spermatogonial differentiation in autocrine- and paracrine-dependent manners.
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Moreau, Evelyne, José Vilar, Martine Lelièvre-Pégorier, Claudie Merlet-Bénichou, and Thierry Gilbert. "Regulation of c-ret expression by retinoic acid in rat metanephros: implication in nephron mass control." American Journal of Physiology-Renal Physiology 275, no. 6 (December 1, 1998): F938—F945. http://dx.doi.org/10.1152/ajprenal.1998.275.6.f938.
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Vitamin A and its derivatives have been shown to promote kidney development in vitro in a dose-dependent fashion. To address the molecular mechanisms by which all- trans-retinoic acid (RA) may regulate the nephron mass, rat kidneys were removed on embryonic day 14( E14) and grown in organ culture under standard or RA-stimulated conditions. By using RT-PCR, we studied the expression of the glial cell line-derived neurotrophic factor (GDNF), its cell surface receptor-α (GDNFR-α), and the receptor tyrosine kinase c-ret, known to play a major role in renal organogenesis. Expression of GDNF and GDNFR-α transcripts was high at the time of explantation and remained unaffected in culture with or without RA. In contrast, c-ret mRNA level, which was low in E14 metanephros and dropped rapidly in vitro, was increased by RA in a dose-dependent manner. The same is true at the protein level. Exogenous GDNF barely promotes additional nephron formation in vitro. Thus the present data establish c-ret as a key target of retinoids during kidney organogenesis.
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Marsh, Debbie J., Zimu Zheng, Andrew Arnold, Scott D. Andrew, Diana Learoyd, Andrea Frilling, Paul Komminoth, et al. "Mutation Analysis of Glial Cell Line-Derived Neurotrophic Factor, a Ligand for an RET/Coreceptor Complex, in Multiple Endocrine Neoplasia Type 2 and Sporadic Neuroendocrine Tumors." Journal of Clinical Endocrinology & Metabolism 82, no. 9 (September 1, 1997): 3025–28. http://dx.doi.org/10.1210/jcem.82.9.4197.
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Abstract Causative germline missense mutations in the RET proto-oncogene have been associated with over 92% of families with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). MEN 2A is characterized primarily by medullary thyroid carcinoma (MTC) and pheochromocytoma, both tumors of neural crest origin. Parathyroid hyperplasia or adenoma is also seen in MEN 2A, but rarely in MEN 2B, which has additional stigmata, including a marfanoid habitus, mucosal neuromas, and ganglioneuromatosis of the gastrointestinal tract. In familial MTC, MTC is the only lesion present. Somatic RET mutations have also been identified in a subset of sporadic MTCs, pheochromocytomas, and rarely, small cell lung cancer, but not in sporadic parathyroid hyperplasias/adenomas or other neuroendocrine tumors. Glial cell line-derived neurotrophic factor (GDNF) and its receptor molecule GDNFR-α, have recently been identified as members of the RET ligand binding complex. Therefore, the genes encoding both GDNF and GDNFR-α are excellent candidates for a role in the pathogenesis of those MEN 2 families and sporadic neuroendocrine tumors without RET mutations. No mutations were found in the coding region of GDNF in DNA samples from 9 RET mutation negative MEN 2 individuals (comprising 6 distinct families), 12 sporadic MTCs, 17 sporadic cases of parathyroid adenoma, and 10 small cell lung cancer cell lines. Therefore, we find no evidence that mutation within the coding regions of GDNF plays a role in the genesis of MEN 2 and sporadic neuroendocrine tumors.
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Walton, Kevin M. "GDNF." Molecular Neurobiology 19, no. 1 (February 1999): 43–59. http://dx.doi.org/10.1007/bf02741377.
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Tao, Le, Wenting Ma, Liu Wu, Mingyi Xu, Yanqin Yang, Wei Zhang, Wenjun Sha, et al. "Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling." Gut 68, no. 12 (June 6, 2019): 2214–27. http://dx.doi.org/10.1136/gutjnl-2018-317872.
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ObjectiveAlthough glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-β superfamily, its function in liver fibrosis has rarely been studied. Here, we investigated the role of GDNF in hepatic stellate cell (HSC) activation and liver fibrosis in humans and mice.DesignGDNF expression was examined in liver biopsies and sera from patients with liver fibrosis. The functional role of GDNF in liver fibrosis was examined in mice with adenoviral delivery of the GDNF gene, GDNF sgRNA CRISPR/Cas9 and the administration of GDNF-blocking antibodies. GDNF was examined on HSC activation using human and mouse primary HSCs. The binding of activin receptor-like kinase 5 (ALK5) to GDNF was determined using surface plasmon resonance (SPR), molecular docking, mutagenesis and co-immunoprecipitation.ResultsGDNF mRNA and protein levels are significantly upregulated in patients with stage F4 fibrosis. Serum GDNF content correlates positively with α-smooth muscle actin (α-SMA) and Col1A1 mRNA in human fibrotic livers. Mice with overexpressed GDNF display aggravated liver fibrosis, while mice with silenced GDNF expression or signalling inhibition by GDNF-blocking antibodies have reduced fibrosis and HSC activation. GDNF is confined mainly to HSCs and contributes to HSC activation through ALK5 at His39 and Asp76 and through downstream signalling via Smad2/3, but not through GDNF family receptor alpha-1 (GFRα1). GDNF, ALK5 and α-SMA colocalise in human and mouse HSCs, as demonstrated by confocal microscopy.ConclusionsGDNF promotes HSC activation and liver fibrosis through ALK5/Smad signalling. Inhibition of GDNF could be a novel therapeutic strategy to combat liver fibrosis.
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Shi, Haikun, Daniel Patschan, Gunnar P. H. Dietz, Mathias Bähr, Matthew Plotkin, and Michael S. Goligorsky. "Glial cell line-derived neurotrophic growth factor increases motility and survival of cultured mesenchymal stem cells and ameliorates acute kidney injury." American Journal of Physiology-Renal Physiology 294, no. 1 (January 2008): F229—F235. http://dx.doi.org/10.1152/ajprenal.00386.2007.
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Glial cell line-derived neurotrophic growth factor (GDNF), a member of the transforming growth factor family, is necessary for renal organogenesis and exhibits changes in expression in models of renal disease. Nestin is an intermediate filament protein originally believed to be a marker of neuroepithelial stem cells and recently proposed as a marker of mesenchymal stem cells (MSC). Having demonstrated the participation of nestin-expressing cells in renoprotection during acute renal ischemia, we hypothesized that growth factors and transcription factors similar to those operating in the nervous system should be also operant in the kidney and may be induced after noxious stimuli, such as an ischemic episode. Using cultured kidney-derived MSC, which abundantly express nestin, we confirmed expression of GDNF by these cells and demonstrated the GDNF-induced expression of GDNF. The cellular expression of nestin paralleled that of GDNF: serum starvation decreased the expression, whereas application of GDNF resulted in a dose-dependent increase in nestin expression. Immunohistochemical and Western blot analyses of kidneys obtained from control and postischemic mice showed that expression of GDNF was much enhanced in the renal cortex, a pattern similar to the previously reported expression of nestin. Based on the observed GDNF-induced GDNF expression, we next explored the effect of supplemental GDNF administered early after ischemia on renal function postischemia. GDNF-treated mice were protected against acute ischemia. To address potential mechanisms of the observed renoprotection, in vitro studies showed that GDNF accelerated MSC migration in a wound-healing assay. Hypoxia did not accelerate, but rather slightly reduced, the motility of MSC and reduced the expression of GDNF in MSC by approximately twofold. Furthermore, GDNF was cytoprotective against oxidative stress-induced apoptotic death of MSC. Collectively, these data establish 1) an autoregulatory circuit of GDNF-induced GDNF expression in renal MSC; 2) induction of GDNF expression in postischemic kidneys; 3) the ability of exogenous GDNF to ameliorate ischemic renal injury; and 4) a possible contribution of GDNF-induced motility and improved survival of MSC to renoprotection.
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Magill, Christina K., Amy M. Moore, Ying Yan, Alice Y. Tong, Matthew R. MacEwan, Andrew Yee, Ayato Hayashi, et al. "The differential effects of pathway- versus target-derived glial cell line–derived neurotrophic factor on peripheral nerve regeneration." Journal of Neurosurgery 113, no. 1 (July 2010): 102–9. http://dx.doi.org/10.3171/2009.10.jns091092.
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Object Glial cell line–derived neurotrophic factor (GDNF) has potent survival effects on central and peripheral nerve populations. The authors examined the differential effects of GDNF following either a sciatic nerve crush injury in mice that overexpressed GDNF in the central or peripheral nervous systems (glial fibrillary acidic protein [GFAP]–GDNF) or in the muscle target (Myo-GDNF). Methods Adult mice (GFAP-GDNF, Myo-GDNF, or wild-type [WT] animals) underwent sciatic nerve crush and were evaluated using histomorphometry and muscle force and power testing. Uninjured WT animals served as controls. Results In the sciatic nerve crush, the Myo-GDNF mice demonstrated a higher number of nerve fibers, fiber density, and nerve percentage (p < 0.05) at 2 weeks. The early regenerative response did not result in superlative functional recovery. At 3 weeks, GFAP-GDNF animals exhibit fewer nerve fibers, decreased fiber width, and decreased nerve percentage compared with WT and Myo-GDNF mice (p < 0.05). By 6 weeks, there were no significant differences between groups. Conclusions Peripheral delivery of GDNF resulted in earlier regeneration following sciatic nerve crush injuries than that with central GDNF delivery. Treatment with neurotrophic factors such as GDNF may offer new possibilities for the treatment of peripheral nerve injury.
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Popsueva, Anna, Dmitry Poteryaev, Elena Arighi, Xiaojuan Meng, Alexandre Angers-Loustau, David Kaplan, Mart Saarma, and Hannu Sariola. "GDNF promotes tubulogenesis of GFRα1-expressing MDCK cells by Src-mediated phosphorylation of Met receptor tyrosine kinase." Journal of Cell Biology 161, no. 1 (April 7, 2003): 119–29. http://dx.doi.org/10.1083/jcb.200212174.
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Glial cell line–derived neurotrophic factor (GDNF) and hepatocyte growth factor (HGF) are multifunctional signaling molecules in embryogenesis. HGF binds to and activates Met receptor tyrosine kinase. The signaling receptor complex for GDNF typically includes both GDNF family receptor α1 (GFRα1) and Ret receptor tyrosine kinase. GDNF can also signal independently of Ret via GFRα1, although the mechanism has remained unclear. We now show that GDNF partially restores ureteric branching morphogenesis in ret-deficient mice with severe renal hypodysplasia. The mechanism of Ret-independent effect of GDNF was therefore studied by the MDCK cell model. In MDCK cells expressing GFRα1 but no Ret, GDNF stimulates branching but not chemotactic migration, whereas both branching and chemotaxis are promoted by GDNF in the cells coexpressing Ret and GFRα1, mimicking HGF/Met responses in wild-type MDCK cells. Indeed, GDNF induces Met phosphorylation in several ret-deficient/GFRα1-positive and GFRα1/Ret-coexpressing cell lines. However, GDNF does not immunoprecipite Met, making a direct interaction between GDNF and Met highly improbable. Met activation is mediated by Src family kinases. The GDNF-induced branching of MDCK cells requires Src activation, whereas the HGF-induced branching does not. Our data show a mechanism for the GDNF-induced branching morphogenesis in non-Ret signaling.
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Cintrón-Colón, Alberto F., Gabriel Almeida-Alves, Alicia M. Boynton, and John M. Spitsbergen. "GDNF synthesis, signaling, and retrograde transport in motor neurons." Cell and Tissue Research 382, no. 1 (September 8, 2020): 47–56. http://dx.doi.org/10.1007/s00441-020-03287-6.
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Abstract Glial cell line–derived neurotrophic factor (GDNF) is a 134 amino acid protein belonging in the GDNF family ligands (GFLs). GDNF was originally isolated from rat glial cell lines and identified as a neurotrophic factor with the ability to promote dopamine uptake within midbrain dopaminergic neurons. Since its discovery, the potential neuroprotective effects of GDNF have been researched extensively, and the effect of GDNF on motor neurons will be discussed herein. Similar to other members of the TGF-β superfamily, GDNF is first synthesized as a precursor protein (pro-GDNF). After a series of protein cleavage and processing, the 211 amino acid pro-GDNF is finally converted into the active and mature form of GDNF. GDNF has the ability to trigger receptor tyrosine kinase RET phosphorylation, whose downstream effects have been found to promote neuronal health and survival. The binding of GDNF to its receptors triggers several intracellular signaling pathways which play roles in promoting the development, survival, and maintenance of neuron-neuron and neuron-target tissue interactions. The synthesis and regulation of GDNF have been shown to be altered in many diseases, aging, exercise, and addiction. The neuroprotective effects of GDNF may be used to develop treatments and therapies to ameliorate neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In this review, we provide a detailed discussion of the general roles of GDNF and its production, delivery, secretion, and neuroprotective effects on motor neurons within the mammalian neuromuscular system.
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Zaman, V., Z. Li, L. Middaugh, S. Ramamoorthy, B. Rohrer, M. E. Nelson, A. C. Tomac, B. J. Hoffer, G. A. Gerhardt, and A. Ch Granholm. "The Noradrenergic System of Aged GDNF Heterozygous Mice." Cell Transplantation 12, no. 3 (April 2003): 291–303. http://dx.doi.org/10.3727/000000003108746740.
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Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for noradrenergic (NE) neurons of the pontine nucleus locus coeruleus (LC). Decreased function of the LC-NE neurons has been found during normal aging and in neurodegenerative disorders. We have previously shown that GDNF participates in the differentiation of LC-NE neurons during development. However, the continued role of GDNF for LC-NE neurons during maturation and aging has not been addressed. We examined alterations in aged mice that were heterozygous for the GDNF gene (Gdnf+/–). Wild-type (Gdnf+/+) and Gdnf+/– mice (18 months old) were tested for locomotor activity and brain tissues were collected for measuring norepinephrine levels and uptake, as well as for morphological analysis. Spontaneous locomotion was reduced in Gdnf+/– mice in comparison with Gdnf+/+ mice. The reduced locomotor activity of Gdnf +/– mice was accompanied by reductions in NE transporter activity in the cerebellum and brain stem as well as decreased norepinephrine tissue levels in the LC. Tyrosine hydroxylase (TH) immunostaining demonstrated morphological alterations of LC-NE cell bodies and abnormal TH-positive fibers in the hippocampus, cerebellum, and frontal cortex of Gdnf+/– mice. These findings suggest that the LC-NE system of Gdnf+/– mice is impaired and suggest that GDNF plays an important role in continued maintenance of this neuronal system throughout life.
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Kitagawa, Hisashi, Chihoko Sasaki, Kenichi Sakai, Atsushi Mori, Yasuhide Mitsumoto, Toyoki Mori, Yoshimosuke Fukuchi, Yasuhiro Setoguchi, and Koji Abe. "Adenovirus-Mediated Gene Transfer of Glial Cell Line-Derived Neurotrophic Factor Prevents Ischemic Brain Injury after Transient Middle Cerebral Artery Occlusion in Rats." Journal of Cerebral Blood Flow & Metabolism 19, no. 12 (December 1999): 1336–44. http://dx.doi.org/10.1097/00004647-199912000-00007.
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To examine a possible protective effect of exogenous glial cell line-derived neurotrophic factor (GDNF) gene expression against ischemic brain injury, a replication-defective adenoviral vector containing GDNF gene (Ad-GDNF) was directly injected into the cerebral cortex at 1 day before 90 minutes of transient middle cerebral artery occlusion (MCAO) in rats. 2,3,5-Triphenyltetrazolium chloride staining showed that infarct volume of the Ad-GDNF-injected group at 24 hours after the transient MCAO was significantly smaller than that of vehicle- or Ad-LacZ-treated group. Enzyme-linked immunosorbent assay (ELISA) for immunoreactive GDNF demonstrated that GDNF gene products in the Ad-GDNF-injected group were higher than those of vehicle-treated group at 24 hours after transient MCAO. Immunoreactive GDNF staining was obviously detected in the cortex around the needle track just before or 24 hours after MCAO in the Ad-GDNF group, whereas no or slight GDNF staining was detected in the vehicle group. The numbers of TUNEL, immunoreactive caspase-3, and cytochrome c-positive neurons induced in the ipsilateral cerebral cortex at 24 hours after transient MCAO were markedly reduced by the Ad-GDNF group. These results suggest that the successful exogenous GDNF gene transfer ameliorates ischemic brain injury after transient MCAO in association with the reduction of apoptotic signals.
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Trupp, M., M. Rydén, H. Jörnvall, H. Funakoshi, T. Timmusk, E. Arenas, and C. F. Ibáñez. "Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons." Journal of Cell Biology 130, no. 1 (July 1, 1995): 137–48. http://dx.doi.org/10.1083/jcb.130.1.137.
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Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic polypeptide, distantly related to transforming growth factor-beta (TGF-beta), originally isolated by virtue of its ability to induce dopamine uptake and cell survival in cultures of embryonic ventral midbrain dopaminergic neurons, and more recently shown to be a potent neurotrophic factor for motorneurons. The biological activities and distribution of this molecule outside the central nervous system are presently unknown. We report here on the mRNA expression, biological activities and initial receptor binding characterization of GDNF and a shorter spliced variant termed GDNF beta in different organs and peripheral neurons of the developing rat. Both GDNF mRNA forms were found to be most highly expressed in developing skin, whisker pad, kidney, stomach and testis. Lower expression was also detected in developing skeletal muscle, ovary, lung, and adrenal gland. Developing spinal cord, superior cervical ganglion (SCG) and dorsal root ganglion (DRG) also expressed low levels of GDNF mRNA. Two days after nerve transection, GDNF mRNA levels increased dramatically in the sciatic nerve. Overall, GDNF mRNA expression was significantly higher in peripheral organs than in neuronal tissues. Expression of either GDNF mRNA isoform in insect cells resulted in the production of indistinguishable mature GDNF polypeptides. Purified recombinant GDNF promoted neurite outgrowth and survival of embryonic chick sympathetic neurons. GDNF produced robust bundle-like, fasciculated outgrowth from chick sympathetic ganglion explants. Although GDNF displayed only low activity on survival of newborn rat SCG neurons, this protein was found to increase the expression of vasoactive intestinal peptide and preprotachykinin-A mRNAs in cultured SCG neurons. GDNF also promoted survival of about half of the neurons in embryonic chick nodose ganglion and a small subpopulation of embryonic sensory neurons in chick dorsal root and rat trigeminal ganglia. Embryonic chick sympathetic neurons expressed receptors for GDNF with Kd 1-5 x 10(-9) M, as measured by saturation and displacement binding assays. Our findings indicate GDNF is a new neurotrophic factor for developing peripheral neurons and suggest possible non-neuronal roles for GDNF in the developing reproductive system.
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Baudet, C., A. Mikaels, H. Westphal, J. Johansen, T. E. Johansen, and P. Ernfors. "Positive and negative interactions of GDNF, NTN and ART in developing sensory neuron subpopulations, and their collaboration with neurotrophins." Development 127, no. 20 (October 15, 2000): 4335–44. http://dx.doi.org/10.1242/dev.127.20.4335.
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Glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN) and neublastin/artemin (ART) are distant members of the transforming growth factor beta family, and have been shown to elicit neurotrophic effects upon several classes of peripheral and central neurons. Limited information from in vitro and expression studies has also substantiated a role for GDNF family ligands in mammalian somatosensory neuron development. Here, we show that although dorsal root ganglion (DRG) sensory neurons express GDNF family receptors embryonically, they do not survive in response to their ligands. The regulation of survival emerges postnatally for all GDNF family ligands. GDNF and NTN support distinct subpopulations that can be separated with respect to their expression of GDNF family receptors, whereas ART supports neurons in populations that are also responsive to GDNF or NTN. Sensory neurons that coexpress GDNF family receptors are medium sized, whereas small-caliber nociceptive cells preferentially express a single receptor. In contrast to brain-derived neurotrophic factor (BDNF)-dependent neurons, embryonic nerve growth factor (NGF)-dependent nociceptive neurons switch dependency to GDNF, NTN and ART postnatally. Neurons that survive in the presence of neurotrophin 3 (NT3) or neurotrophin 4 (NT4), including proprioceptive afferents, Merkel end organs and D-hair afferents, are also supported by GDNF family ligands neonatally, although at postnatal stages they lose their dependency on GDNF and NTN. At late postnatal stages, ART prevents survival elicited by GDNF and NTN. These data provide new insights on the roles of GDNF family ligands in sensory neuron development.
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Huang, Ssu-Ming, Tzu-Sheng Chen, Chien-Ming Chiu, Leang-Kai Chang, Kuan-Fu Liao, Hsiao-Ming Tan, Wei-Lan Yeh, Gary Ro-Lin Chang, Min-Ying Wang, and Dah-Yuu Lu. "GDNF increases cell motility in human colon cancer through VEGF–VEGFR1 interaction." Endocrine-Related Cancer 21, no. 1 (October 28, 2013): 73–84. http://dx.doi.org/10.1530/erc-13-0351.
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Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor, has been shown to affect cancer cell metastasis and invasion. However, the molecular mechanisms underlying GDNF-induced colon cancer cell migration remain unclear. GDNF is found to be positively correlated with malignancy in human colon cancer patients. The migratory activities of two human colon cancer cell lines, HCT116 and SW480, were found to be enhanced in the presence of human GDNF. The expression of vascular endothelial growth factor (VEGF) was also increased in response to GDNF stimulation, along with VEGF mRNA expression and transcriptional activity. The enhancement of GDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Our results also showed that the expression of VEGF receptor 1 (VEGFR1) was increased in response to GDNF stimulation, whereas GDNF-induced cancer cell migration was reduced by a VEGFR inhibitor. The GDNF-induced VEGF expression was regulated by the p38 and PI3K/Akt signaling pathways. Treatment with GDNF increased nuclear hypoxia-inducible factor 1 α (HIF1α) accumulation and its transcriptional activity in a time-dependent manner. Moreover, GDNF increased hypoxia responsive element (HRE)-containing VEGF promoter transcriptional activity but not that of the HRE-deletion VEGF promoter construct. Inhibition of HIF1α by a pharmacological inhibitor or dominant-negative mutant reduced the GDNF-induced migratory activity in human colon cancer cells. These results indicate that GDNF enhances the migration of colon cancer cells by increasing VEGF–VEGFR interaction, which is mainly regulated by the p38, PI3K/Akt, and HIF1α signaling pathways.
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Meir, Michael, Sven Flemming, Natalie Burkard, Lisa Bergauer, Marco Metzger, Christoph-Thomas Germer, and Nicolas Schlegel. "Glial cell line-derived neurotrophic factor promotes barrier maturation and wound healing in intestinal epithelial cells in vitro." American Journal of Physiology-Gastrointestinal and Liver Physiology 309, no. 8 (October 15, 2015): G613—G624. http://dx.doi.org/10.1152/ajpgi.00357.2014.
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Recent data suggest that neurotrophic factors from the enteric nervous system are involved in intestinal epithelial barrier regulation. In this context the glial cell line-derived neurotrophic factor (GDNF) was shown to affect gut barrier properties in vivo directly or indirectly by largely undefined processes in a model of inflammatory bowel disease (IBD). We further investigated the potential role and mechanisms of GDNF in the regulation of intestinal barrier functions. Immunostaining of human gut specimen showed positive GDNF staining in enteric neuronal plexus and in enterocytes. In Western blots of the intestinal epithelial cell lines Caco2 and HT29B6, significant amounts of GDNF were detected, suggesting that enterocytes represent an additional source of GDNF. Application of recombinant GDNF on Caco2 and HT29B6 cells for 24 h resulted in significant epithelial barrier stabilization in monolayers with immature barrier functions. Wound-healing assays showed a significantly faster closure of the wounded areas after GDNF application. GDNF augmented cAMP levels and led to significant inactivation of p38 MAPK in immature cells. Activation of p38 MAPK signaling by SB-202190 mimicked GDNF-induced barrier maturation, whereas the p38 MAPK activator anisomycin blocked GDNF-induced effects. Increasing cAMP levels had adverse effects on barrier maturation, as revealed by permeability measurements. However, increased cAMP augmented the proliferation rate in Caco2 cells, and GDNF-induced proliferation of epithelial cells was abrogated by the PKA inhibitor H89. Our data show that enterocytes represent an additional source of GDNF synthesis. GDNF contributes to wound healing in a cAMP/PKA-dependent manner and promotes barrier maturation in immature enterocytes cells by inactivation of p38 MAPK signaling.
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Wang, Feng, Nana Li, Ruanling Hou, Lu Wang, Libin Zhang, Chenzhang Li, Yu Zhang, et al. "Treatment of Parkinson’s disease using focused ultrasound with GDNF retrovirus-loaded microbubbles to open the blood–brain barrier." Open Chemistry 18, no. 1 (August 3, 2020): 882–89. http://dx.doi.org/10.1515/chem-2020-0142.
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AbstractThis study aims to prepare ultrasound-targeted glial cell-derived neurotrophic factor (GDNF) retrovirus-loaded microbubbles (M pLXSN-GDNF) to verify the properties of the microbubbles and to study the therapeutic effect of the GDNF retrovirus-loaded microbubbles combined with ultrasound (U) to open the blood–brain barrier (BBB) in a Parkinson’s disease (PD) model in rats, allowing the retrovirus to pass through the BBB and transfect neurons in the substantia nigra of the midbrain, thereby increasing the expression of GDNF. The results of western blot analysis revealed significant differences between U + MpLXSN-EGFP, U + M + pLXSN-GDNF, and M pLXSN-GDNF (P < 0.05) groups. After 8 weeks of treatment, the evaluation of the effect of increased GDNF expression on behavioral deficits in PD model rats was conducted. The rotation symptom was significantly improved in the U + MpLXSN-GDNF group, and the difference before and after treatment was significant (P < 0.05). Also, the content of dopamine and the number of tyrosine hydroxylase-positive (dopaminergic) neurons were found to be higher in the brain of PD rats in the U + M pLXSN-GDNF group than in the control groups. Ultrasound combined with GDNF retrovirus-loaded microbubbles can enhance the transfection efficiency of neurons in vivo and highly express the exogenous GDNF gene to play a therapeutic role in PD model rats.
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Wong, Chee Ern David, Khang Hua, Simon Monis, Anwar Norazit, Suzita Mohd Noor, and Marc Ekker. "Cellular Localization of gdnf in Adult Zebrafish Brain." Brain Sciences 10, no. 5 (May 11, 2020): 286. http://dx.doi.org/10.3390/brainsci10050286.
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Glial cell line-derived neurotrophic factor (GDNF) was initially described as important for dopaminergic neuronal survival and is involved in many other essential functions in the central nervous system. Characterization of GDNF phenotype in mammals is well described; however, studies in non-mammalian vertebrate models are scarce. Here, we characterized the anatomical distribution of gdnf-expressing cells in adult zebrafish brain by means of combined in situ hybridization (ISH) and immunohistochemistry. Our results revealed that gdnf was widely dispersed in the brain. gdnf transcripts were co-localized with radial glial cells along the ventricular area of the telencephalon and in the hypothalamus. Interestingly, Sox2 positive cells expressed gdnf in the neuronal layer but not in the ventricular zone of the telencephalon. A subset of GABAergic precursor cells labeled with dlx6a-1.4kbdlx5a/6a: green fluorescence protein (GFP) in the pallium, parvocellular preoptic nucleus, and the anterior and dorsal zones of the periventricular hypothalamus also showed expression with gdnf mRNA. In addition, gdnf signals were detected in subsets of dopaminergic neurons, including those in the ventral diencephalon, similar to what is seen in mammalian brain. Our work extends our knowledge of gdnf action sites and suggests a potential role for gdnf in adult brain neurogenesis and regeneration.
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Gao, Xiaoqing, Li Deng, Yun Wang, Ling Yin, Chaoxian Yang, Jie Du, and Qionglan Yuan. "GDNF Enhances Therapeutic Efficiency of Neural Stem Cells-Based Therapy in Chronic Experimental Allergic Encephalomyelitis in Rat." Stem Cells International 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/1431349.
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Multiple sclerosis (MS) is an autoimmune disease in the CNS. The current immunomodulating drugs for MS do not effectively prevent the progressive neurological decline. Neural stem cells (NSCs) transplantation has been proven to promote repair and functional recovery of experimental allergic encephalomyelitis (EAE) animal model for MS, and glial cell line-derived neurotrophic factor (GDNF) has also been found to have capability of promoting axonal regeneration and remyelination of regenerating axons. In the present study, to assess whether GDNF would enhance therapeutic effect of NSCs for EAE, GDNF gene-modified NSCs (GDNF/NSCs) and native NSCs were transplanted into each lateral ventricle of rats at 10 days and rats were sacrificed at 60 days after EAE immunization. We found that NSCs significantly reduced the clinical signs, and GDNF gene-modification further promoted functional recovery. GDNF/NSCs more profoundly suppressed brain inflammation and improved density of myelin compared with NSCs. The survival of GDNF/NSCs was significantly higher than that of transplanted NSCs. Transplanted GDNF/NSCs, in contrast to NSCs, differentiated into more neurons and oligodendrocytes. Moreover, the mRNA expression of oligodendrocyte lineage cells in rats with GDNF/NSCs was significantly increased compared to rats with NSCs. These results suggest that GDNF enhances therapeutic efficiency of NSCs-based therapy for EAE.
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Alfano, Ivan, Parvez Vora, Rosemary S. Mummery, Barbara Mulloy, and Christopher C. Rider. "The major determinant of the heparin binding of glial cell-line-derived neurotrophic factor is near the N-terminus and is dispensable for receptor binding." Biochemical Journal 404, no. 1 (April 26, 2007): 131–40. http://dx.doi.org/10.1042/bj20061747.
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GDNF (glial cell-line-derived neurotrophic factor), and the closely related cytokines artemin and neurturin, bind strongly to heparin. Deletion of a basic amino-acid-rich sequence of 16 residues N-terminal to the first cysteine of the transforming growth factor β domain of GDNF results in a marked reduction in heparin binding, whereas removal of a neighbouring sequence, and replacement of pairs of other basic residues with alanine had no effect. The heparin-binding sequence is quite distinct from the binding site for the high affinity GDNF polypeptide receptor, GFRα1 (GDNF family receptor α1), and heparin-bound GDNF is able to bind GFRα1 simultaneously. The heparin-binding sequence of GDNF is dispensable both for GFRα1 binding, and for activity for in vitro neurite outgrowth assay. Surprisingly, the observed inhibition of GDNF bioactivity with the wild-type protein in this assay was still found with the deletion mutant lacking the heparin-binding sequence. Heparin neither inhibits nor potentiates GDNF–GFRα1 interaction, and the extracellular domain of GFRα1 does not bind to heparin itself, precluding heparin cross-bridging of cytokine and receptor polypeptides. The role of heparin and heparan sulfate in GDNF signalling remains unclear, but the present study indicates that it does not occur in the first step of the pathway, namely GDNF–GFRα1 engagement.
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Lee, Bun-Hee, Jin-Pyo Hong, Jung-A. Hwang, Kyoung-Sae Na, Won-Joong Kim, Jose Trigo, and Yong-Ku Kim. "Plasma glial cell line-derived neurotrophic factor in patients with major depressive disorder: a preliminary study." Acta Neuropsychiatrica 28, no. 1 (June 30, 2015): 45–50. http://dx.doi.org/10.1017/neu.2015.42.
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BackgroundSome clinical studies have reported reduced peripheral glial cell line-derived neurotrophic factor (GDNF) level in elderly patients with major depressive disorder (MDD). We verified whether a reduction in plasma GDNF level was associated with MDD.MethodPlasma GDNF level was measured in 23 healthy control subjects and 23 MDD patients before and after 6 weeks of treatment.ResultsPlasma GDNF level in MDD patients at baseline did not differ from that in healthy controls. Plasma GDNF in MDD patients did not differ significantly from baseline to the end of treatment. GDNF level was significantly lower in recurrent-episode MDD patients than in first-episode patients before and after treatment.ConclusionsOur findings revealed significantly lower plasma GDNF level in recurrent-episode MDD patients, although plasma GDNF levels in MDD patients and healthy controls did not differ significantly. The discrepancy between our study and previous studies might arise from differences in the recurrence of depression or the ages of the MDD patients.
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Troshina, A. A., A. A. Shpak, A. B. Guekht, T. A. Druzhkova, and N. V. Gulyaeva. "Neurotrophic factors in patients with primary open-angle glaucoma and age-related cataract. Part 3. Glial-derived neurotrophic factor." Fyodorov journal of ophthalmic surgery, no. 4 (December 19, 2022): 45–50. http://dx.doi.org/10.25276/0235-4160-2022-4-45-50.
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Purpose. To evaluate content of glial-derived neurotrophic factor (GDNF) in the aqueous humor (AH), lacrimal fluid (LF), and blood serum (BS) in patients with primary open-angle glaucoma (POAG) and agerelated cataract. Material and methods. A comprehensive examination of a group of patients with POAG in combination with age-related cataract was carried out. As a comparison group, previously examined patients with age-related cataract were taken. The content of GDNF in the LF, AH and BS was studied in all patients. Collection of stimulated LF was performed with a pipette dispenser on the day preceding surgery; the AH and BS were sampled during the phacoemulsification of a cataract. The concentration of GDNF was measured using an enzyme immunoassay. Results. At the early stages of POAG (stages 1–2 according to classification by Mills et al, 2006) there was a significant decrease in the level of GDNF in all studied biological fluids, especially pronounced in the AH and LF – about 2 times (P <0.001); the decrease of GDNF in the BS was less than 20% (P <0.05). In stages 3-4, the GDNF levels consistently increased; the levels of GDNF in the LF and AH remained significantly reduced in comparison with patients without glaucoma. An inverse correlation with the perimetric index VFI was found for the content of GDNF in LF and BS; a direct correlation was found between the GDNF levels in BS and AH. Conclusion. In patients with POAG, a significant decrease of GDNF content in the LF, AH and BS was revealed, especially in the early stages of the disease. In subsequent stages, reduction of GDNF levels in the AH and LF was consistently less significant. With the disease progression, there is a gradual increase in the concentration of GDNF in the AH and LF; nevertheless, the level of GDNF in these fluids remains significantly reduced compared to patients without glaucoma. An inverse correlation with the perimetric index VFI was found for the content of GDNF in LF and BS, as well as a direct correlation of GDNF levels in the BS and AH. Key words: glial-derived neurotrophic factor, primary open-angle glaucoma, age-related cataract, lacrimal fluid, aqueous humor, blood serum.
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Alvarez, Pedro, Xiaojie Chen, Oliver Bogen, Paul G. Green, and Jon D. Levine. "IB4(+) nociceptors mediate persistent muscle pain induced by GDNF." Journal of Neurophysiology 108, no. 9 (November 1, 2012): 2545–53. http://dx.doi.org/10.1152/jn.00576.2012.
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Skeletal muscle is a well-known source of glial cell line-derived neurotrophic factor (GDNF), which can produce mechanical hyperalgesia. Since some neuromuscular diseases are associated with both increased release of GDNF and intense muscle pain, we explored the role of GDNF as an endogenous mediator in muscle pain. Intramuscularly injected GDNF induced a dose-dependent (0.1–10 ng/20 μl) persistent (up to 3 wk) mechanical hyperalgesia in the rat. Once hyperalgesia subsided, injection of prostaglandin E2 at the site induced a prolonged mechanical hyperalgesia (>72 h) compared with naïve rats (<4 h; hyperalgesic priming). Selective neurotoxic destruction of IB4(+) nociceptors attenuated both GDNF hyperalgesia and hyperalgesic priming. Ergonomic muscular injury induced by eccentric exercise or mechanical vibration increased muscle GDNF levels at 24 h, a time point where rats also exhibited marked muscle hyperalgesia. Intrathecal antisense oligodeoxynucleotides to mRNA encoding GFRα1, the canonical binding receptor for GDNF, reversibly inhibited eccentric exercise- and mechanical vibration-induced muscle hyperalgesia. Finally, electrophysiological recordings from nociceptors innervating the gastrocnemius muscle in anesthetized rats, revealed significant increase in response to sustained mechanical stimulation after local GDNF injection. In conclusion, these data indicate that GDNF plays a role as an endogenous mediator in acute and induction of chronic muscle pain, an effect likely to be produced by GDNF action at GFRα1 receptors located in IB4(+) nociceptors.
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Emerich, Dwaine F., Jeffrey H. Kordower, Yaping Chu, Chris Thanos, Briannan Bintz, Giovanna Paolone, and Lars U. Wahlberg. "Widespread Striatal Delivery of GDNF from Encapsulated Cells Prevents the Anatomical and Functional Consequences of Excitotoxicity." Neural Plasticity 2019 (March 11, 2019): 1–9. http://dx.doi.org/10.1155/2019/6286197.
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Methods. Human ARPE-19 cells engineered to secrete high levels of the glial cell line-derived neurotrophic factor (GDNF) were encapsulated into hollow fiber membranes. The devices were implanted into the rat striatum 1 week prior to striatal quinolinic acid injections. Animals were evaluated using a battery of validated motor tests, and histology was performed to determine the extent of GDNF diffusion and associated prevention of neuronal cell loss and behavioral deficits. Results. Encapsulated cell-based delivery of GDNF produced widespread distribution of GDNF throughout the entire implanted striatum. Stereological estimates of striatal neuron number and volume of lesion size revealed that GDNF delivery resulted in near complete neuroprotection. Conclusions. Delivery of neurotrophic molecules such as GDNF using encapsulated cells has reached a technological point where clinical evaluation is justified. Because GDNF has been effective in animal models of Parkinson’s disease, stroke, epilepsy, and Huntington’s disease, among other debilitating neurodegenerative diseases, encapsulated cell-based delivery of GDNF might represent one innovative means of slowing the neural degeneration seen in a myriad of currently untreatable neurological diseases.
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Peterziel, H., K. Unsicker, and K. Krieglstein. "TGFβ induces GDNF responsiveness in neurons by recruitment of GFRα1 to the plasma membrane." Journal of Cell Biology 159, no. 1 (October 7, 2002): 157–67. http://dx.doi.org/10.1083/jcb.200203115.
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We have previously shown that the neurotrophic effect of glial cell line–derived neurotrophic factor (GDNF) in vitro and in vivo requires the presence of transforming growth factor (TGF)β. Using primary neurons (chick E8 ciliary) we show that the combination of GDNF plus TGFβ promotes survival, whereas the single factors do not. This cooperative effect is inhibited by blocking the extracellular signal-regulated kinase (ERK)/MAPK pathway, but not by interfering with the PI3 kinase signaling cascade. Although there is no functional GDNF signaling in the absence of TGFβ, pretreatment with TGFβ confers GDNF responsiveness to the cells. This is not due to upregulation of GDNF receptors mRNA and protein, but to TGFβ-induced recruitment of the glycosyl-phosphatidylinositol-anchored GDNF receptor (GFR)α1 to the plasma membrane. This is supported by the fact that GDNF in the presence of a soluble GFRα1 can promote survival in the absence of TGFβ. Our data suggest that TGFβ is involved in GFRα1 membrane translocation, thereby permitting GDNF signaling and neurotrophic effects.
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Xia, Siwen, Mingxing Zhang, Meng Li, Xianmin Song, Donghui Chen, Minhui Zhu, Hongliang Zheng, and Shicai Chen. "The Bridging Effect of Controlled-Release Glial Cell-Derived Neurotrophic Factor Microcapsules within Nerve Conduits on Rat Facial Nerve Regeneration." Disease Markers 2022 (June 21, 2022): 1–7. http://dx.doi.org/10.1155/2022/8942985.
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Objectives. The study is aimed at exploring the effect of the controlled release of the glial-derived neurotrophic factor (GDNF) on nerve regeneration. Methods. The PLGA/chitosan composite nerve conduit was used to bridge the dissected trunk of the rat facial nerve. GDNF microcapsules were loaded into the nerve conduit. Nine weeks after surgery, the facial nerve zygomatic and buccal branches were labeled with fluorescent indicators. The incorrectly grown facial neurons were reversed and counted. The facial nerve functional recovery was assessed by measuring the maximum evoked potential. Results. The nerve conduit was filled with different regenerating factors, such as the GDNF, GDNF microcapsules, or saline (control). The number of incorrectly regenerated neurons was lower with the nerve conduits filled with GDNF microcapsules than with those supplied with just the GDNF. However, neither the GDNF nor GDNF microcapsules affected the number of regenerated neurons. The functional recovery of the facial nerve was the best, with the nerve conduit filled with GDNF microcapsules closest to the healthy uncut facial nerve. Conclusion. The stable slow-release GNDF microcapsule inside the biodegradable nerve conduit can reduce the extent of incorrect growth of the facial nerve neuron when bridging the dissected rat facial nerve trunk. The technique has a good effect on functional nerve recovery.
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Gao, Xiaoqing, Guangqiang Hu, Li Deng, Guangbi Fan, Chaoxian Yang, and Jie Du. "Transplantation of Neural Stem Cells Cotreated with Thyroid Hormone and GDNF Gene Induces Neuroprotection in Rats of Chronic Experimental Allergic Encephalomyelitis." Neural Plasticity 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/3081939.
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The present study investigates whether transplantation of NSCs treated with T3 alone (T3/NSCs), or in conjunction with GDNF gene (GDNF-T3/NSCs), provides a better therapeutic effect than NSCs for chronic EAE. EAE rats were, respectively, injected with NSCs, T3/NSCs, GDNF-T3/NSCs, and saline at 10 days and sacrificed at 60 days after EAE immunization. The three cell grafted groups showed a significant reduction in clinical scores, inflammatory infiltration, and demyelination compared with the saline-injected group, and among the cell grafted groups, the reduction in GDNF-T3/NSCs group was the most notable, followed by T3/NSCs group. Grafted T3/NSCs and GDNF-T3/NSCs acquired more MAP2, GalC, and less GFAP in brain compared with grafted NSCs, and grafted GDNF-T3/NSCs acquired most MAP2 and least GalC among the cell grafted groups. Furthermore, T3/NSCs and GDNF-T3/NSCs grafting increased the expression of mRNA for PDGFαR, GalC, and MBP in lesion areas of brain compared with NSCs grafting, and the expression of mRNA for GalC and MBP in GDNF-T3/NSCs group was higher than that in T3/NSCs group. In conclusion, T3/NSCs grafting, especially GDNF-T3/NSCs grafting, provides a better neuroprotective effect for EAE than NSCs transplantation.
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Tsybko, Anton S., Tatiana V. Ilchibaeva, and Nina K. Popova. "Role of glial cell line-derived neurotrophic factor in the pathogenesis and treatment of mood disorders." Reviews in the Neurosciences 28, no. 3 (April 1, 2017): 219–33. http://dx.doi.org/10.1515/revneuro-2016-0063.
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AbstractGlial cell line-derived neurotrophic factor (GDNF) is widely recognized as a survival factor for dopaminergic neurons, but GDNF has also been shown to promote development, differentiation, and protection of other central nervous system neurons and was thought to play an important role in various neuropsychiatric disorders. Severe mood disorders, such as primarily major depressive disorder and bipolar affective disorder, attract particular attention. These psychopathologies are characterized by structural alterations accompanied by the dysregulation of neuroprotective and neurotrophic signaling mechanisms required for the maturation, growth, and survival of neurons and glia. The main objective of this review is to summarize the recent findings and evaluate the potential role of GDNF in the pathogenesis and treatment of mood disorders. Specifically, it describes (1) the implication of GDNF in the mechanism of depression and in the effect of antidepressant drugs and mood stabilizers and (2) the interrelation between GDNF and brain neurotransmitters, playing a key role in the pathogenesis of depression. This review provides converging lines of evidence that (1) brain GDNF contributes to the mechanism underlying depressive disorders and the effect of antidepressants and mood stabilizers and (2) there is a cross-talk between GDNF and neurotransmitters representing a feedback system: GDNF-neurotransmitters and neurotransmitters-GDNF.
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Wang, Li, Zheng Gao, Gang Chen, Deqin Geng, and Dianshuai Gao. "Low Levels of Adenosine and GDNF Are Potential Risk Factors for Parkinson’s Disease with Sleep Disorders." Brain Sciences 13, no. 2 (January 24, 2023): 200. http://dx.doi.org/10.3390/brainsci13020200.
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Sleep disturbances are the most prevalent non-motor symptoms in the preclinical stage of Parkinson’s disease (PD). Adenosine, glial-derived neurotrophic factor (GDNF), and associated neurotransmitters are crucial in the control of sleep arousal. This study aimed to detect the serum levels of adenosine, GDNF, and associated neurotransmitters and explored their correlations with PD with sleep disorders. Demographic characteristics and clinical information of PD patients and healthy participants were assessed. Serum concentrations of adenosine, GDNF, and related neurotransmitters were detected by ELISA and LC-MS. The correlation between serum levels of adenosine, GDNF, and associated neurotransmitters and sleep disorders was explored using logistic regression. PD patients with sleep disorders had higher scores of HAMA, HAMD, ESS, UPDRS-III, and H-Y stage. Lower levels of adenosine, GDNF, and γ-GABA were observed in PD patients who had sleep problems. Logistic regression analysis showed adenosine and GDNF were protective factors for preventing sleep disorders. Adenosine combined with GDNF had a higher diagnostic efficiency in predicting PD with sleep disorders by ROC analysis. This study revealed low adenosine and GDNF levels may be risk factors for sleep disorders in PD. The decrease of serum adenosine and GDNF levels may contribute to the diagnosis of PD with sleep disturbances.
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Nakao, Naoyuki, Hideyuki Yokote, Kunio Nakai, and Toru Itakura. "Promotion of survival and regeneration of nigral dopamine neurons in a rat model of Parkinson's disease after implantation of embryonal carcinoma—derived neurons genetically engineered to produce glial cell line—derived neurotrophic factor." Journal of Neurosurgery 92, no. 4 (April 2000): 659–70. http://dx.doi.org/10.3171/jns.2000.92.4.0659.
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Object. The P19 embryonal carcinoma—derived cell line consists of undifferentiated multipotential cells, which irreversibly differentiate into mature neurons after exposure to retinoic acid (RA). In the present study, the authors genetically engineered P19 cells to produce glial cell line—derived neurotrophic factor (GDNF), and grafted the cells in a rat model that had been rendered parkinsonian.Methods. Undifferentiated P19 cells were grown in vitro and transduced with GDNF complementary DNA. The level of GDNF released from the transduced cells was measured using an enzyme-linked immunosorbent assay, and its neurotrophic activities were assessed by testing the effects on rat embryonic dopamine (DA) neurons in culture. After having been exposed to RA for 48 hours and allowed to differentiate into postmitotic neurons, the GDNF gene—transduced cells were implanted into the midbrain of immunosuppressed rats. A unilateral nigrostriatal lesion was then induced by intrastriatal infusions of 6-hydroxydopamine. Immunohistochemical analyses performed 4 weeks postgrafting revealed that the GDNF-producing cells expressed several neuronal markers without evidence of overgrowth. The grafts expressed GDNF protein and prevented the death of nigral DA neurons. Furthermore, the GDNF-producing cells implanted 4 weeks after nigrostriatal lesions restored the expression of tyrosine hydroxylase in injured DA neurons and induced their dendritic sprouting.Conclusions. The results indicate that the P19 cell line transduced with the GDNF gene can stably secrete functional levels of GDNF, even after being converted to postmitotic neurons. Because it is has been established that GDNF exerts trophic effects on DA neurons, the means currently used to deliver GDNF into the brain could be a viable strategy to prevent the death of nigral DA neurons in cases of Parkinson's disease.
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Jing, Shuqian, Duanzhi Wen, Yanbin Yu, Paige L. Holst, Yi Luo, Mei Fang, Rami Tamir, et al. "GDNF–Induced Activation of the Ret Protein Tyrosine Kinase Is Mediated by GDNFR-α, a Novel Receptor for GDNF." Cell 85, no. 7 (June 1996): 1113–24. http://dx.doi.org/10.1016/s0092-8674(00)81311-2.
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Drinkut, Anja, Karsten Tillack, Durga P. Meka, Jorg B. Schulz, Sebastian Kügler, and Edgar R. Kramer. "Ret is essential to mediate GDNF’s neuroprotective and neuroregenerative effect in a Parkinson disease mouse model." Cell Death & Disease 7, no. 9 (September 2016): e2359-e2359. http://dx.doi.org/10.1038/cddis.2016.263.
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Abstract Glial cell line-derived neurotrophic factor (GDNF) is a potent survival and regeneration-promoting factor for dopaminergic neurons in cell and animal models of Parkinson disease (PD). GDNF is currently tested in clinical trials on PD patients with so far inconclusive results. The receptor tyrosine kinase Ret is the canonical GDNF receptor, but several alternative GDNF receptors have been proposed, raising the question of which signaling receptor mediates here the beneficial GDNF effects. To address this question we overexpressed GDNF in the striatum of mice deficient for Ret in dopaminergic neurons and subsequently challenged these mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Strikingly, in this established PD mouse model, the absence of Ret completely abolished GDNF’s neuroprotective and regenerative effect on the midbrain dopaminergic system. This establishes Ret signaling as absolutely required for GDNF’s effects to prevent and compensate dopaminergic system degeneration and suggests Ret activation as the primary target of GDNF therapy in PD.
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Meir, Michael, Felix Kannapin, Markus Diefenbacher, Yalda Ghoreishi, Catherine Kollmann, Sven Flemming, Christoph-Thomas Germer, et al. "Intestinal Epithelial Barrier Maturation by Enteric Glial Cells Is GDNF-Dependent." International Journal of Molecular Sciences 22, no. 4 (February 14, 2021): 1887. http://dx.doi.org/10.3390/ijms22041887.
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Enteric glial cells (EGCs) of the enteric nervous system are critically involved in the maintenance of intestinal epithelial barrier function (IEB). The underlying mechanisms remain undefined. Glial cell line-derived neurotrophic factor (GDNF) contributes to IEB maturation and may therefore be the predominant mediator of this process by EGCs. Using GFAPcre x Ai14floxed mice to isolate EGCs by Fluorescence-activated cell sorting (FACS), we confirmed that they synthesize GDNF in vivo as well as in primary cultures demonstrating that EGCs are a rich source of GDNF in vivo and in vitro. Co-culture of EGCs with Caco2 cells resulted in IEB maturation which was abrogated when GDNF was either depleted from EGC supernatants, or knocked down in EGCs or when the GDNF receptor RET was blocked. Further, TNFα-induced loss of IEB function in Caco2 cells and in organoids was attenuated by EGC supernatants or by recombinant GDNF. These barrier-protective effects were blunted when using supernatants from GDNF-deficient EGCs or by RET receptor blockade. Together, our data show that EGCs produce GDNF to maintain IEB function in vitro through the RET receptor.
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Michel, Tanja M., Sophia Frangou, Sibylle Camara, Dorothea Thiemeyer, Julia Jecel, Thomas Tatschner, Robert Zoechling, and Edna Grünblatt. "Altered glial cell line-derived neurotrophic factor (GDNF) concentrations in the brain of patients with depressive disorder: A comparative post-mortem study." European Psychiatry 23, no. 6 (September 2008): 413–20. http://dx.doi.org/10.1016/j.eurpsy.2008.06.001.
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AbstractIntroductionA growing body of evidence suggests that the glial cell line-derived neurotrophic factor (GDNF) is involved in the aetiopathology of mood disorders. GDNF is a neurotrophic factor from the transforming growth factor-β-family, playing a role in cell development and function in the limbic system. This is the first study to examine GDNF concentration in different brain regions of patients with depressive disorder (DD).Material and MethodsWe used sandwich-ELISA-technique to ascertain GDNF concentration and Lowry assay for overall protein levels in post-mortem brain tissue of 7 patients with recurrent depressive disorder and 14 individuals without any neurological or psychiatric diagnoses. We included cortical regions as well as limbic area's (hippocampus, entorhinal cortex) basal ganglia (putamen, caudate nucleus), thalamus and cingulated gyrus.ResultsWe found a significant increase in GDNF concentration in the parietal cortex of patients with DD compared to the control group. In other regions the trend of an increased GDNF concentration did not reach statistical difference.DiscussionThis proof of concept study supports previous findings of an alteration of the GDNF in patients with depressive disorder. However, for the first time a significant increase of GDNF in a cortical brain area was found in DD.
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Mwangi, Simon Musyoka, Sophia Peng, Behtash Ghazi Nezami, Natalie Thorn, Alton B. Farris, Sanjay Jain, Hamed Laroui, Didier Merlin, Frank Anania, and Shanthi Srinivasan. "Glial cell line-derived neurotrophic factor protects against high-fat diet-induced hepatic steatosis by suppressing hepatic PPAR-γ expression." American Journal of Physiology-Gastrointestinal and Liver Physiology 310, no. 2 (January 15, 2016): G103—G116. http://dx.doi.org/10.1152/ajpgi.00196.2015.
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Glial cell line-derived neurotrophic factor (GDNF) protects against high-fat diet (HFD)-induced hepatic steatosis in mice, however, the mechanisms involved are not known. In this study we investigated the effects of GDNF overexpression and nanoparticle delivery of GDNF in mice on hepatic steatosis and fibrosis and the expression of genes involved in the regulation of hepatic lipid uptake and de novo lipogenesis. Transgenic overexpression of GDNF in liver and other metabolically active tissues was protective against HFD-induced hepatic steatosis. Mice overexpressing GDNF had significantly reduced P62/sequestosome 1 protein levels suggestive of accelerated autophagic clearance. They also had significantly reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) and CD36 gene expression and protein levels, and lower expression of mRNA coding for enzymes involved in de novo lipogenesis. GDNF-loaded nanoparticles were protective against short-term HFD-induced hepatic steatosis and attenuated liver fibrosis in mice with long-standing HFD-induced hepatic steatosis. They also suppressed the liver expression of steatosis-associated genes. In vitro, GDNF suppressed triglyceride accumulation in Hep G2 cells through enhanced p38 mitogen-activated protein kinase-dependent signaling and inhibition of PPAR-γ gene promoter activity. These results show that GDNF acts directly in the liver to protect against HFD-induced cellular stress and that GDNF may have a role in the treatment of nonalcoholic fatty liver disease.
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Wei, Guo-Jun, Gang An, Zuo-Wei Shi, Kai-Fu Wang, Ying Guan, Yan-Song Wang, Bo Han, et al. "Suppression of MicroRNA-383 Enhances Therapeutic Potential of Human Bone-Marrow-Derived Mesenchymal Stem Cells in Treating Spinal Cord Injury via GDNF." Cellular Physiology and Biochemistry 41, no. 4 (2017): 1435–44. http://dx.doi.org/10.1159/000468057.
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Background/Aims: Transplantation of bone-marrow-derived mesenchymal stem cells (MSCs) has been used to treat spinal cord injury (SCI) to enhance tissue repair and neural cell regeneration. Glial cell line derived neurotrophic factor (GDNF) is an identified neural growth and survival factor. Here, we examined whether modification of GDNF levels in MSCs may further increase the potential of MSCs in promoting neural cell regeneration and subsequently the therapeutic outcome. Methods: We examined the mRNA and protein levels of GDNF in human MSCs by RT-qPCR and Western blot, respectively. Bioinformatics analyses were done to predict microRNAs (miRNAs) that target GDNF in MSCs. The functional binding of miRNAs to GDNF mRNA was examined by a dual luciferase reporter assay. MSCs were transduced with adeno-associated virus (AAV) carrying null or antisense for miR-383 (as-miR-383), which were transplanted into nude rats that underwent SCI. The intact tissue, cavity volume, and recovery of locomotor activity were assessed. Results: MSCs expressed very low GDNF protein, but surprisingly high levels of GDNF mRNA. Bioinformatics analyses showed that miR-383 inhibited protein translation of GDNF, through binding to the 3’-UTR of the GDNF mRNA. MSCs transduced with AAV-as-miR-383 further increased the intact tissue percentage, decreased cavity volume, and enhanced the recovery of locomotor activity in nude rats that underwent SCI, compared to MSCs. Conclusions: Suppression of miR-383 may increase the therapeutic potential of human bone-marrow-derived MSCs in treating SCI via augmentation of GDNF protein levels.
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Farhadi, Shaheen, Adithya Gopinath, Wolfgang Streit, Gregory A. Hudalla, and Habibeh Khoshbouei. "4053 A TL1 Team Approach to CNS-Localized Delivery of Glial Cell-Derived Neurotrophic Factor for Treatment of Parkinson’s Disease." Journal of Clinical and Translational Science 4, s1 (June 2020): 1. http://dx.doi.org/10.1017/cts.2020.49.
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OBJECTIVES/GOALS: Develop a strategy to restrict GDNF diffusion at an injected CNS tissue site for dopamine neuron rescue by endowing it with binding affinity for carbohydrates that are abundant on the cell surface and extracellular matrix. METHODS/STUDY POPULATION: GDNF will be fused to galectin-3 (G3), a human protein that binds to β-galactoside residues of cell surface and matrix glycoproteins. We characterized the binding of G3 fusion proteins to various glycoproteins and primary human myeloid cells. We incubated G3 fusions with CNS tissue ex vivo to measure their binding and depth of penetration via diffusion. We next plan to administer GDNF-G3 via CNS intracranial infusion in a murine PD model and then conduct behavioral PD phenotype testing via rotarod and pole descent to compare to non-parkinsonian controls. We will further examine the effects of GDNF-G3 on degeneration using immunohistochemical examination of post-mortem brain tissue. RESULTS/ANTICIPATED RESULTS: Based on results from previous clinical trials of GDNF delivery, we anticipate that a successful intervention using GDNF-G3 will result in rescue of midbrain dopaminergic neurons in a murine PD model. In murine CNS tissue, we observed binding to glycans at the tissue surfaces when incubated with G3 fusion proteins ex vivo, suggesting GDNF-G3 will remain localized to the injection site. Next we will administer GDNF-G3 via CNS intracranial infusion in a murine PD model and assess efficacy by behavior and histopathology. GDNF-G3-mediated dopamine neuron rescue are expected to slow or reverse the progression of PD in these animal models. DISCUSSION/SIGNIFICANCE OF IMPACT: PD treatments focus on symptomatic relief. Standard therapies have not been efficacious in rescuing of dopaminergic neurons. GDNF-G3 administered at the site of neurodegeneration would represent a milestone on the path to treating PD pathology and address limitations of GDNF delivery.
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Cheng, Fu-Chou, Ming-Hong Tai, Meei-Ling Sheu, Chun-Jung Chen, Dar-Yu Yang, Hong-Lin Su, Shu-Peng Ho, Shu-Zhen Lai, and Hung-Chuan Pan. "Enhancement of regeneration with glia cell line–derived neurotrophic factor–transduced human amniotic fluid mesenchymal stem cells after sciatic nerve crush injury [RETRACTED]." Journal of Neurosurgery 112, no. 4 (April 2010): 868–79. http://dx.doi.org/10.3171/2009.8.jns09850.
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Object Human amniotic fluid–derived mesenchymal stem cells (AFMSCs) have been shown to promote peripheral nerve regeneration, and the local delivery of neurotrophic factors may additionally enhance nerve regeneration capacity. The present study evaluates whether the transplantation of glia cell line–derived neurotrophic factor (GDNF)–modified human AFMSCs may enhance regeneration of sciatic nerve after a crush injury. Methods Peripheral nerve injury was produced in Sprague-Dawley rats by crushing the left sciatic nerve using a vessel clamp. Either GDNF-modified human AFMSCs or human AFMSCs were embedded in Matrigel and delivered to the injured nerve. Motor function and electrophysiological studies were conducted after 1 and 4 weeks. Early or later nerve regeneration markers were used to evaluate nerve regeneration. The expression of GDNF in the transplanted human AFMSCs and GDNF-modified human AFMSCs was monitored at 7-day intervals. Results Human AFMSCs were successfully transfected with adenovirus, and a significant amount of GDNF was detected in human AFMSCs or the culture medium supernatant. Increases in the sciatic nerve function index, the compound muscle action potential ratio, conduction latency, and muscle weight were found in the groups treated with human AFMSCs or GDNF-modified human AFMSCs. Importantly, the GDNF-modified human AFMSCs induced the greatest improvement. Expression of markers of early nerve regeneration, such as increased expression of neurofilament and BrdU and reduced Schwann cell apoptosis, as well as late regeneration markers, consisting of reduced vacuole counts, increased expression of Luxol fast blue and S100 protein, paralleled the results of motor function. The expression of GDNF in GDNF-modified human AFMSCs was demonstrated up to 4 weeks; however, the expression decreased over time. Conclusions The GDNF-modified human AFMSCs appeared to promote nerve regeneration. The consecutive expression of GDNF was demonstrated in GDNF-modified human AFMSCs up to 4 weeks. These findings support a nerve regeneration scenario involving cell transplantation with additional neurotrophic factor secretion.
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Sharma, A., S. M. Shah, N. Saini, M. K. Singh, S. K. Singla, P. Palta, R. S. Manik, and M. S. Chauhan. "230 EFFECT OF DIFFERENT CONCENTRATIONS OF GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR ON EXPRESSION OF SELF-RENEWAL RELATED GENES IN GOAT (CAPRA HIRCUS) SPERMATOGONIAL STEM CELLS." Reproduction, Fertility and Development 28, no. 2 (2016): 246. http://dx.doi.org/10.1071/rdv28n2ab230.
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Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor-β superfamily produced by Sertoli cells, is essential for the self-renewal of spermatogonial stem cells in vivo. The present study evaluated the effects of different concentrations of GDNF (human recombinant expressed in Escherichia coli) on expression of some self-renewal related genes in spermatogonial stem cells (SSC). The SSC were isolated from prepubertal goat testes (3–6 months of age) by using double enzymatic digestion method and filtration through 80- and 60-µm nylon mesh filters. Further enrichment was achieved by differential plating on Datura stramonium agglutinin (DSA) lectin-coated dishes and Percoll density gradient centrifugation. The enriched cells were cultured on goat Sertoli cell feeder layer in DMEM + 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Primary SSC colonies were formed within 7 to 10 days. These colonies were characterised through alkaline phosphatase and immunofluorescence staining on Day 10 for different SSC-specific protein markers. Colonies were found to be positive for DBA, THY1, PLZF, UCHL1, OCT-4, SOX2, and NANOG, and negative for c-Kit expression. These colonies were cultured for 15 days without or with supplementation of GDNF forming following groups: (1) without GDNF (control), (2) 10 ng mL–1 GDNF, (3) 20 ng mL–1 GDNF, and (4) 40 ng mL–1 GDNF. RNA was isolated from 100 colonies from 3 different trials on Day 15 of culture, and relative expression of different self-renewal related genes was determined by qRT-PCR. Relative mRNA abundance of PLZF was higher (P < 0.05) following supplementation with 40 ng mL–1 GDNF than in other groups (i.e. control, 10 and 20 ng mL–1 GDNF). Expression of BCL6B and ID4 was found to be significantly higher (P < 0.05) after supplementation of GDNF at all concentrations compared with the control group. Expression of UCHL1 was higher with addition of 20 and 40 ng mL–1 GDNF (P < 0.05), whereas expression of THY1 was higher with supplementation of 10 ng mL–1 GDNF (P < 0.05). In conclusion, GDNF was found to benefit expression of goat SSC candidate genes at a concentration of 40 ng mL–1.
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Yasuhara, Takao, Tetsuro Shingo, Kenichiro Muraoka, Kazuki Kobayashi, Akira Takeuchi, Akimasa Yano, Yuan WenJi, et al. "Early transplantation of an encapsulated glial cell line—derived neurotrophic factor—producing cell demonstrating strong neuroprotective effects in a rat model of Parkinson disease." Journal of Neurosurgery 102, no. 1 (January 2005): 80–89. http://dx.doi.org/10.3171/jns.2005.102.1.0080.
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Object. Glial cell line—derived neurotrophic factor (GDNF) has been shown to confer neuroprotective effects on dopaminergic neurons. The authors investigated the effects of GDNF on 6-hydroxydopamine (6-OHDA)—treated dopaminergic neurons in vitro and in vivo. Methods. First, the authors examined how 1, 10, or 100 ng/ml of GDNF, administered to cells 24 hours before, simultaneously with, or 2 or 4 hours after 6-OHDA was added, affected dopaminergic neurons. In a primary culture of E14 murine ventral mesencephalic neurons, earlier treatment with the higher dosage of GDNF suppressed 6-OHDA—induced loss of dopaminergic neurons better than later treatment. Next, the authors examined whether continuous infusion of GDNF at earlier time points would demonstrate a greater neuroprotective effect in a rat model of Parkinson disease (PD). They established a human GDNF-secreting cell line, called BHK-GDNF, and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally implanted into the striatum of adult rats 1 week before; simultaneously with; or 1, 2, or 4 weeks after 6-OHDA was given to induce lesions of the same striatum. With the earlier transplantation of a BHK-GDNF capsule, there was a significant reduction in the number of amphetamine-induced rotations displayed by the animals. Rats that had received earlier implantation of BHK-GDNF capsules displayed more tyrosine hydroxylase—positive neurons in the substantia nigra pars compacta and a tendency for glial proliferation in the striatum. Conclusions. These neuroprotective effects may be related to glial proliferation and signaling via the GDNF receptor α1. The results of this study support a role for this grafting technique in the treatment of PD.
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Japón, Miguel A., Angel G. Urbano, Carmen Sáez, Dolores I. Segura, Alfonso Leal Cerro, Carlos Diéguez, and Clara V. Alvarez. "Glial-Derived Neurotropic Factor and RET Gene Expression in Normal Human Anterior Pituitary Cell Types and in Pituitary Tumors." Journal of Clinical Endocrinology & Metabolism 87, no. 4 (April 1, 2002): 1879–84. http://dx.doi.org/10.1210/jcem.87.4.8383.
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Abstract Glial-derived neurotropic factor (GDNF) signaling is mediated through a 2-component system consisting of the so-called GDNF receptor-α (GFRα1), which binds to GDNF. This complex activates the tyrosine kinase receptor RET. In this paper we demonstrate GDNF, GFRα1, and RET mRNA and protein expression in the human anterior pituitary gland. Double immunohistochemistry of anterior pituitary sections showed GDNF immunoreactivity in more than 95% of somatotrophs and to a lesser extent in corticotrophs (20%); it was almost absent in the remaining cell types. Also, although more than 95% of somatotrophs were stained for RET, no positive immunostaining could be detected in other cell types. Furthermore, we have looked for GDNF and RET in human pituitary adenomas of various hormonal phenotypes. Strong positive immunostaining was found for c-RET in all of the GH-secreting adenomas screened as well as in 50% of ACTH-producing adenomas. Positive immunostaining for GDNF was found in all of the GH-secreting adenomas and in 10% of the corticotropinomas. Lastly, we found strong positive immunostaining for GFRα1 in 90% of the somatotropinomas and 50% of the corticotropinomas as well as in 1 of 8 prolactinomas and 1 of 13 nonfunctioning adenomas. All of the remaining pituitary tumors screened were negative for RET, GDNF, and GFRα1. This study indicates that GDNF may well be acting in the regulation of somatotroph cell growth and/or cell function in the normal human anterior pituitary gland. The expression of RET in all of the somatotropinomas and in 50% of the ACTH-producing tumors implies that GDNF and RET could be involved in the pathogenesis of pituitary tumors.
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Mwangi, Simon M., Yousef Usta, Shreya M. Raja, Mallappa Anitha, Bindu Chandrasekharan, Alexander Parsadanian, Shanthi V. Sitaraman, and Shanthi Srinivasan. "Glial cell line-derived neurotrophic factor enhances neurogenin3 gene expression and β-cell proliferation in the developing mouse pancreas." American Journal of Physiology-Gastrointestinal and Liver Physiology 299, no. 1 (July 2010): G283—G292. http://dx.doi.org/10.1152/ajpgi.00096.2010.
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Glial cell line-derived neurotrophic factor (GDNF) is a factor produced by glial cells that is required for the development of the enteric nervous system. In transgenic mice that overexpress GDNF in the pancreas, GDNF has been shown to enhance β-cell mass and improve glucose control, but the transcriptional and cellular processes involved are not known. In this study we examined the influence of GDNF on the expression of neurogenin3 (Ngn3) and other transcription factors implicated in early β-cell development, as well as on β-cell proliferation during embryonic and early postnatal mouse pancreas development. Embryonic day 15.5 (E15.5) mouse pancreatic tissue when exposed to GDNF for 24 h showed higher Ngn3, pancreatic and duodenal homeobox gene 1 (Pdx1), neuroD1/β2, paired homeobox gene 4 (Pax4), and insulin mRNA expression than tissue exposed to vehicle only. Transgenic expression of GDNF in mouse pancreata was associated with increased numbers of Ngn3-expressing pancreatic cells and higher β-cell mass at embryonic day 18 (E18), as well as higher β-cell proliferation and Pdx1 expression in β-cells at E18 and postnatal day 1. In the HIT-T15 β-cell line, GDNF enhanced the expression of Pax6. This response was, however, blocked in the presence of Pdx1 small interfering RNA (siRNA). Chromatin immunoprecipitation studies using the HIT-T15 β-cell line demonstrated that GDNF can influence Pdx1 gene expression by enhancing the binding of Sox9 and neuroD1/β2 to the Pdx1 promoter. Our data provide evidence of a mechanism by which GDNF influences β-cell development. GDNF could be a potential therapeutic target for the treatment and prevention of diabetes.
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Duarte Azevedo, Marcelo, Sibilla Sander, and Liliane Tenenbaum. "GDNF, A Neuron-Derived Factor Upregulated in Glial Cells during Disease." Journal of Clinical Medicine 9, no. 2 (February 7, 2020): 456. http://dx.doi.org/10.3390/jcm9020456.
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In a healthy adult brain, glial cell line-derived neurotrophic factor (GDNF) is exclusively expressed by neurons, and, in some instances, it has also been shown to derive from a single neuronal subpopulation. Secreted GDNF acts in a paracrine fashion by forming a complex with the GDNF family receptor α1 (GFRα1), which is mainly expressed by neurons and can act in cis as a membrane-bound factor or in trans as a soluble factor. The GDNF/GFRα1 complex signals through interactions with the “rearranged during transfection” (RET) receptor or via the neural cell adhesion molecule (NCAM) with a lower affinity. GDNF can also signal independently from GFRα1 by interacting with syndecan-3. RET, which is expressed by neurons involved in several pathways (nigro–striatal dopaminergic neurons, motor neurons, enteric neurons, sensory neurons, etc.), could be the main determinant of the specificity of GDNF’s pro-survival effect. In an injured brain, de novo expression of GDNF occurs in glial cells. Neuroinflammation has been reported to induce GDNF expression in activated astrocytes and microglia, infiltrating macrophages, nestin-positive reactive astrocytes, and neuron/glia (NG2) positive microglia-like cells. This disease-related GDNF overexpression can be either beneficial or detrimental depending on the localization in the brain and the level and duration of glial cell activation. Some reports also describe the upregulation of RET and GFRα1 in glial cells, suggesting that GDNF could modulate neuroinflammation.
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Zhao, Yuling, Matthew J. Haney, John K. Fallon, Myosotys Rodriguez, Carson J. Swain, Camryn J. Arzt, Philip C. Smith, et al. "Using Extracellular Vesicles Released by GDNF-Transfected Macrophages for Therapy of Parkinson Disease." Cells 11, no. 12 (June 15, 2022): 1933. http://dx.doi.org/10.3390/cells11121933.
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Extracellular vesicles (EVs) are cell-derived nanoparticles that facilitate transport of proteins, lipids, and genetic material, playing important roles in intracellular communication. They have remarkable potential as non-toxic and non-immunogenic nanocarriers for drug delivery to unreachable organs and tissues, in particular, the central nervous system (CNS). Herein, we developed a novel platform based on macrophage-derived EVs to treat Parkinson disease (PD). Specifically, we evaluated the therapeutic potential of EVs secreted by autologous macrophages that were transfected ex vivo to express glial-cell-line-derived neurotrophic factor (GDNF). EV-GDNF were collected from conditioned media of GDNF-transfected macrophages and characterized for GDNF content, size, charge, and expression of EV-specific proteins. The data revealed that, along with the encoded neurotrophic factor, EVs released by pre-transfected macrophages carry GDNF-encoding DNA. Four-month-old transgenic Parkin Q311(X)A mice were treated with EV-GDNF via intranasal administration, and the effect of this therapeutic intervention on locomotor functions was assessed over a year. Significant improvements in mobility, increases in neuronal survival, and decreases in neuroinflammation were found in PD mice treated with EV-GDNF. No offsite toxicity caused by EV-GDNF administration was detected. Overall, an EV-based approach can provide a versatile and potent therapeutic intervention for PD.
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Pascual, Alberto, María Hidalgo-Figueroa, Raquel Gómez-Díaz, and José López-Barneo. "GDNF and protection of adult central catecholaminergic neurons." Journal of Molecular Endocrinology 46, no. 3 (February 28, 2011): R83—R92. http://dx.doi.org/10.1530/jme-10-0125.
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Neurotrophic factors are small proteins necessary for neuron survival and maintenance of phenotype. They are considered as promising therapeutic tools for neurodegenerative diseases. The glial cell line-derived neurotrophic factor (GDNF) protects catecholaminergic cells from toxic insults; thus, its potential therapeutic applicability in Parkinson's disease has been intensely investigated. In recent years, there have been major advances in the analysis of GDNF signaling pathways in peripheral neurons and embryonic dopamine mesencephalic cells. However, the actual physiological role of GDNF in maintaining catecholaminergic central neurons during adulthood is only starting to be unraveled, and the mechanisms whereby GDNF protects central brain neurons are poorly known. In this study, we review the current knowledge of GDNF expression, signaling, and function in adult brain, with special emphasis on the genetic animal models with deficiency in the GDNF-dependent pathways.
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Kelm, M., N. Burkard, M. Hoerner, C. T. Germer, N. Schlegel, and S. Flemming. "P002 Glial cell line-Derived Neurotrophic Factor (GDNF) improves intestinal wound healing – A new target for IBD treatment?" Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i135—i136. http://dx.doi.org/10.1093/ecco-jcc/jjab232.131.
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Abstract Background Due to the rising incidence and socioeconomic relevance of Inflammatory Bowel Disease (IBD) worldwide, new therapeutic strategies are necessary to improve patient care. Since immunosuppressants are partially insufficient with relevant rates of side effects, novel concepts of treatment need to be developed. Mucosal and/or histological healing represent potential criteria to measure disease activity and are mentioned in current guidelines as favorable prognostic factors regarding disease outcomes. In previous studies, the soluble factor Glial cell line-Derived Neurotrophic Factor (GDNF) has been shown to be significantly reduced in tissue specimens from IBD patients and to be critically involved in intestinal epithelial barrier maturation. Therefore, the goal of this study was to further analyze the potential role of GDNF in IBD. Methods Intestinal wound healing was assessed in endoscopic biopsy-based wound assays as well as dextran sodium sulphate (DSS)-induced colitis in vivo. During the experiments, C57Bl/6 mice were either injected with GDNF or sodium chloride intraperitoneal while tissue samples were used for detailed molecular analyses. Further, scratch wound assays were performed in Caco2 monolayers to identify molecular pathways and cell mechanisms in vitro. Results Intraperitoneal injection of GDNF resulted in significantly enhanced wound closure in vivo. During the DSS-induced colitis model, mice treated with GDNF demonstrated significantly improved recovery from colitis in comparison to mice injected with sodium chloride. Similarly, application of GDNF in a scratch wound assay significantly enhanced wound closure in vitro. Mechanistically, molecular analysis revealed that GDNF application resulted in significantly increased cell proliferation. The effect of GDNF on cell proliferation was based on upregulation of LGR5-positive cells with increased phosphorylation of pSrc. Further studies demonstrated that the effect of GDNF on wound healing and cell proliferation could be inhibited by application of a Src-inhibitor. Conclusion GDNF significantly improves intestinal mucosal healing in vivo and in vitro which results in significantly enhanced recovery from colitis. While this effect is driven by increased cell proliferation due to upregulation of LGR5-positive cells and increased phosphorylation of pSrc, previous studies already demonstrated the critical impact of GDNF on epithelial barrier function. Following that, GDNF might have great potential in IBD treatment and could be a new target for future therapeutic approaches.
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Dong, Zhiqiang, Yong Sun, Peihua Lu, Yanqing Wang, and Gencheng Wu. "Electroacupuncture and Lumbar Transplant of GDNF-Secreting Fibroblasts Synergistically Attenuate Hyperalgesia after Sciatic Nerve Constriction." American Journal of Chinese Medicine 41, no. 03 (January 2013): 459–72. http://dx.doi.org/10.1142/s0192415x1350033x.
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Electroacupuncture (EA) has been shown to induce potent analgesic effects on neuropathic pain in both patients and rodents. Cell therapy to release antinociceptive agents near the pain processing centers of the spinal cord is a promising next step in the development of treatment modalities. This study investigated the effects of the combination of EA and cell therapy by glial cell line-derived neurotrophic factor (GDNF) on neuropathic pain in rats. The hyperalgesic state was induced by chronic constriction injury (CCI) of the sciatic nerve and fibroblasts genetically modified to secrete bioactive GDNF (FBs-GDNF) were used for cell therapy. Fifty-eight rats with neuropathic pain were randomly divided into five groups (CCI+PBS, n = 11; CCI+FBs-GDNF, n = 12; CCI+EA+PBS, n = 11; CCI+EA+FBs-pLNCX2, n = 12; CCI+EA+FBs-GDNF, n = 12). On the 7th day after CCI, the rats received intrathecal transplantation of FBs-GDNF or control fibroblasts (FBs-pLNCX2). In the meantime, EA was administered once every other day from the 7th day after CCI surgery for 21 days. The paw withdrawal latency (PWL) to radiant heat was measured every other day. The results showed that the ipsilateral PWL of the rats from all three EA treatment groups significantly increased starting on the 12th day compared with the PBS control group. Strikingly, the group which received EA treatment and FBs-GDNF transplantation (CCI+EA+FBs-GDNF) showed a significantly decreased thermal hyperalgesia after 2 weeks post CCI surgery compared with the groups which received EA treatment and FBs-pLNCX2 transplantation (CCI+EA+FBs-pLNCX2) or PBS (CCI+EA+PBS) as well as the FBs-GDNF transplantation group without EA treatment (CCI+FBs-GDNF). Our data suggest that EA and cell therapy can synergistically attenuate hyperalgesia in neuropathic pain rats.
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Linher, Katja, De Wu, and Julang Li. "Glial Cell Line-Derived Neurotrophic Factor: An Intraovarian Factor that Enhances Oocyte Developmental Competence in Vitro." Endocrinology 148, no. 9 (September 1, 2007): 4292–301. http://dx.doi.org/10.1210/en.2007-0021.
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The success of early embryonic development depends on oocyte nuclear and cytoplasmic maturation. We have investigated whether glial cell line-derived neurotrophic factor (GDNF) affects the in vitro maturation (IVM) of porcine oocytes and their subsequent ability to sustain preimplantation embryo development. GDNF and both its coreceptors, GDNF family receptor α-1 (GFRα-1) and the rearranged during transformation (RET) receptor, were expressed in oocytes and their surrounding cumulus cells derived from small and large follicles. When included in IVM medium, GDNF significantly enhanced cumulus cell expansion of both small and large cumulus-oocyte complexes and increased the percentage of small follicle-derived oocytes maturing to the metaphase II stage, although nuclear maturation of large oocytes was not significantly affected. Examination of cyclin B1 protein expression as a measure of cytoplasmic maturation revealed that in the presence of GDNF, cyclin B1 levels were significantly increased in large follicle-derived oocytes, as well as in oocytes from small follicles to a level comparable to the untreated large group. After activation, a significantly higher percentage of both small and large oocytes that were matured in the presence of GDNF developed to the blastocyst stage compared with untreated controls. Indeed, GDNF enhanced the blastocyst rate of small oocytes to levels comparable to those obtained for large oocytes matured without GDNF. The effect of GDNF was specific; this was evident because its enhancement of nuclear maturation and embryo developmental potential was blocked by an antibody against GFRα-1. Our study provides the first functional evidence that GDNF affects oocyte maturation and preimplantation embryo developmental competence in a follicular stage-dependent manner. This finding may provide insights for improving the formulation of IVM culture systems, especially for oocytes from small follicles.
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Meir, Michael, Sven Flemming, Natalie Burkard, Johanna Wagner, Christoph-Thomas Germer, and Nicolas Schlegel. "The glial cell-line derived neurotrophic factor: a novel regulator of intestinal barrier function in health and disease." American Journal of Physiology-Gastrointestinal and Liver Physiology 310, no. 11 (June 1, 2016): G1118—G1123. http://dx.doi.org/10.1152/ajpgi.00125.2016.
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Regulation of the intestinal epithelial barrier is a differentiated process, which is profoundly deranged in inflammatory bowel diseases. Recent data provide evidence that the glial cell line-derived neurotrophic factor (GDNF) is critically involved in intestinal epithelial wound healing and barrier maturation and exerts antiapoptotic effects under certain conditions. Furthermore, not only the enteric nervous system, but also enterocytes synthesize GDNF in significant amounts, which points to a potential para- or autocrine signaling loop between enterocytes. Apart from direct effects of GDNF on enterocytes, an immunomodulatory role of this protein has been previously assumed because of a significant reduction of inflammation in a model of chronic inflammatory bowel disease after application of GDNF. In this review we summarize the current knowledge of GDNF on intestinal epithelial barrier regulation and discuss the novel role for GDNF as a regulator of intestinal barrier functions in health and disease.
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Fromont-Hankard, Gaelle, Pascale Philippe-Chomette, Anne-Lise Delezoide, Catherine Nessmann, Yves Aigrain, and Michel Peuchmaur. "Glial Cell–Derived Neurotrophic Factor Expression in Normal Human Lung and Congenital Cystic Adenomatoid Malformation." Archives of Pathology & Laboratory Medicine 126, no. 4 (April 1, 2002): 432–36. http://dx.doi.org/10.5858/2002-126-0432-gcdnfe.
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Abstract Context.—It has been recently suggested that dysregulation of developmental factors and disruption of cell turnover could play a role in the pathogenesis of congenital cystic adenomatoid malformation of the lung (CCAM). The glial cell–derived neurotrophic factor (GDNF) is a growth factor involved in organogenesis, and the temporal pattern of GDNF expression suggests that this factor may play a role in lung development. Design.—We studied GDNF expression by immunohistochemistry in postnatally resected CCAM of the lung (n = 10), normal fetal lung (n = 5), and normal postnatal lung (n = 5). We also studied the association between GDNF expression and both cell proliferation and apoptosis. Results.—GDNF was expressed in both epithelial and endothelial compartments of normal fetal lung, whereas no expression was found in normal postnatal lung. In contrast, in CCAM tissue, there was strong GDNF immunostaining that was restricted to epithelial cells. The percentage of proliferating epithelial cells was higher in CCAM tissue than in normal postnatal lung (6.3% vs 1.7%, P < .005). Apoptotic bodies were found in the mesenchyme of both normal fetal lung and CCAM tissue, whereas virtually no apoptotic bodies were detected in normal postnatal lung. Conclusions.—Abnormal GDNF expression in CCAM suggests a dysregulation of the GDNF signaling pathway and argues in favor of a focal arrest in maturation during development. GDNF expression in lung tissue seems to be correlated with cell proliferation, suggesting that this factor could play a role in the growth of both fetal lung and CCAM.
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Fouchécourt, Sophie, Murielle Godet, Odile Sabido, and Philippe Durand. "Glial cell-line-derived neurotropic factor and its receptors are expressed by germinal and somatic cells of the rat testis." Journal of Endocrinology 190, no. 1 (July 2006): 59–71. http://dx.doi.org/10.1677/joe.1.06699.
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Glial cell-line-derived neurotropic factor (GDNF) and its receptors glial cell-line-derived neurotropic factor α (GFR1α) and rearranged during transformation (RET) have been localized in the rat testis during postnatal development. The three mRNAs, and GDNF and GFR1α proteins were detected in testis extracts from 1- to 90-day-old rats by reverse transcriptase PCR and Western blotting respectively. The three mRNAs were present in Sertoli cells from 20- and 55-day-old rats, pachytene spermatocytes (PS), and round spermatids (RS). The GDNF and GFR1α proteins were detected in PS, RS, and Sertoli cells. GDNF and GFR1α were also detected using flow cytometry in spermatogonia and preleptotene spermatocytes, and in secondary spermatocytes. The localization of GDNF and GFR1α in germ and Sertoli cells was confirmed by immunocytochemistry. The hypothesis that GDNF may control DNA synthesis of Sertoli cells and/or spermatogonia in the immature rat was addressed using cultures of seminiferous tubules from 7- to 8-day-old rats. Addition of GDNF for 48 h resulted in a twofold decrease in the percentage of spermatogonia able to duplicate DNA, whereas Sertoli cells were not affected. These results are consistent with a role of GDNF in inhibiting the S-phase entrance of a large subset of differentiated type A spermatogonia, together with an enhancing effect of the factor on a small population of undifferentiated (stem cells) spermatogonia. Moreover, the wide temporal and spatial expression of GDNF and its receptors in the rat testis suggest that it might act at several stages of spermatogenesis.