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1
Poudel, Phanindra Prasad, Chacchu Bhattarai, Arnab Ghosh, and Sneha Guruprasad Kalthur. "Expression of ATOH1 gene and activated signaling pathways for the neurogenesis of cerebellar granule cells: A review." Neuroscience Research Notes 5, no. 2 (April 28, 2022): 125. http://dx.doi.org/10.31117/neuroscirn.v5i2.125.
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Granule cells in the cerebellum are derived by the proliferation of cells from the rhombic lips of the metencephalon. Atonal homolog 1 (ATOH1), a protein encoding proneural gene, plays an essential role in the neurogenesis of the cerebellar granule cells. It encodes the basic helix loop helix (bHLH) family of transcription factor ATOH1. Expression of the ATOH1 gene in the rhombic lips of the metencephalon results in specification and proliferation of the granule neuron progenitors. Four major signaling pathways- Sonic hedgehog (Shh), Notch, Wingless related integration site (Wnt) and Bone morphogenetic protein (BMP) play an essential role in the regulation of the ATOH1 gene. Shh, Notch and Wnt signalings induce expression of the ATOH1 gene for the proliferation of the granule neuron progenitors whereas BMP signaling is involved in the differentiation of the granule neuron progenitors into the granule cells. Aberrant expression and mutation of the ATOH1 gene result in cerebellar medulloblastoma, the phenotype of trembling gait, cerebellar ataxia and hearing loss.
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Gao, W. Q., and M. E. Hatten. "Immortalizing oncogenes subvert the establishment of granule cell identity in developing cerebellum." Development 120, no. 5 (May 1, 1994): 1059–70. http://dx.doi.org/10.1242/dev.120.5.1059.
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After implantation into the external germinal layer of early postnatal cerebellum, primary external germinal layer progenitor cells gave rise exclusively to granule neurons. In contrast, all major classes of cerebellar cells were observed following implantation of embryonic day 13 cerebellar precursor cells into the external germinal layer. These results suggest that granule cells arise from precursors with a restricted potential. In contrast to results with the primary external germinal layer population, cell lines established from external germinal layer cells, by infection with a retrovirus containing the SV40 large T-antigen oncogene, gave rise to several cerebellar cell types upon implantation. These included granule neurons, one subclass of stellate interneurons, Golgi cells, Bergmann glia and astrocytes. From these results, we conclude that early postnatal external germinal layer progenitors are normally fated to a granule cell identity and that expression of the SV40 large T-antigen oncogene subverts mechanisms that control granule neuron fate.
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Aiello, Giuseppe, and Luca Tiberi. "TMOD-05. IN VIVO REPROGRAMMING OF POSTMITOTIC NEURONS INDUCES MEDULLOBLASTOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi263. http://dx.doi.org/10.1093/neuonc/noz175.1104.
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Abstract It is widely accepted that the “cell of origin” of tumors has to possess a proliferative capacity. Particularly for brain cancer, the transition of neural progenitors to differentiated postmitotic neurons is considered irreversible in physiological and pathological conditions. Therefore, postmitotic neurons have not been considered as suitable cell-of-origin for brain cancer. Here, we show that neurons reprograming may occur upon Shh activation and it leads to medulloblastoma (MB) formation in vivo. Shh MB is a cerebellar tumor, found in infants and adults that is thought to originate from cerebellar granule neuron progenitors. More recently, it was discovered that the two different forms of SHH MB are distinguished by different transcriptome/methylome levels suggesting that the adult SHH MB may originate from a different cell-of-origin. Relying on these data, we take advantage of a conditional Cre-Lox recombination system to recapitulate the human adult medulloblastoma pathogenesis in mice and demonstrate that post-migratory mature granule neurons can be reprogrammed in vivo. Furthermore, to define the contribution of chromatin changes in granule neurons dedifferentiation in response to Shh activation, we profiled changes in chromatin accessibility by ATAC-seq both in mouse tissue samples and also in human neurons. Upon Shh pathway activation we detected the presence of hyper-accessible chromatin regions corresponding to cis-regulatory elements specifically favouring activation of enhancers and super-enhancers. Our novel model of cancer development could explain the human SHH medulloblastoma onset in adult individuals where granule neuron progenitors are no more present. We strongly believe that our model represents an important starting point to study other tissues where postmitotic cells might originate cancer and therefore open a new field in cancer and stem cell biology.
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Mayerl, Steffen, Andrea Alcaide Martin, Reinhard Bauer, Markus Schwaninger, Heike Heuer, and Charles ffrench-Constant. "Distinct Actions of the Thyroid Hormone Transporters Mct8 and Oatp1c1 in Murine Adult Hippocampal Neurogenesis." Cells 11, no. 3 (February 2, 2022): 524. http://dx.doi.org/10.3390/cells11030524.
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Inactivating mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) result in Allan-Herndon-Dudley Syndrome, a severe form of psychomotor retardation, while inactivating mutations in another TH transporter, organic anion transporting polypeptide 1c1 (OATP1C1), are linked to juvenile neurodegeneration. These diseases point to essential roles for TH transporters in CNS function. We recently defined the presence of Mct8 in adult hippocampal progenitors and mature granule cell neurons and unraveled cell-autonomous and indirect requirements for Mct8 in adult hippocampal neurogenesis. Here, we investigated whether Oatp1c1 is involved in the hippocampal neurogenic process in concert with Mct8. We detected Oatp1c1 gene expression activity and transcripts in subsets of progenitors, neurons and niche cells in the dentate gyrus. Absence of Oatp1c1 resulted in increased neuroblast and reduced immature neuron numbers in 6-month-old Oatp1c1ko and Mct8/Oatp1c1 double knockout (M/Odko) mice. Reduced EdU-label retention in Mct8ko and M/Odko mice confirmed the impact of Mct8 on neuron formation. In contrast, no significant effect of Oatp1c1 loss on granule cell neuron production and anxiety-like behavior in the open field arena were seen. Together, our results reinforce that distinct actions of each TH transporter are required at multiple stages to ensure proper adult hippocampal neurogenesis.
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Cui, Hong, and Robert F. Bulleit. "Potassium chloride inhibits proliferation of cerebellar granule neuron progenitors." Developmental Brain Research 106, no. 1-2 (March 1998): 129–35. http://dx.doi.org/10.1016/s0165-3806(97)00204-6.
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Yang, X. W., R. Zhong, and N. Heintz. "Granule cell specification in the developing mouse brain as defined by expression of the zinc finger transcription factor RU49." Development 122, no. 2 (February 1, 1996): 555–66. http://dx.doi.org/10.1242/dev.122.2.555.
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The creation of specific neuronal cell types within the developing brain is a critical and unsolved biological problem. Precedent from invertebrate development, and from vertebrate myogenesis and lymphogenesis, has established that cell specification often involves transcription factors that are expressed throughout the differentiation of a given cell type. In this study, we have identified in Zn2+ finger transcription factor RU49 as a definitive marker for the cerebellar granule neuron lineage. Thus, RU49 is expressed in the earliest granule cell progenitors at the rhombic lip as they separate from the ventricular zone of the neural tube to generate a secondary proliferative matrix, and it continues to be expressed in differentiating and mature granule neurons. Proliferating granule cell progenitors isolated from the rhombic lip at E14 or from the external germinal layer at P6 continue to express RU49 in vitro. Both the olfactory bulb and dentate gyrus granule cell lineages also express this factor as they are generated with the developing brain. RU49 binds a novel bipartite DNA-binding element in a manner consistent with chemical rules governing the DNA-binding specificity of this class of transcription factor. The novel biochemical properties of RU49 and its restricted expression within the three lineages of CNS granule neurons suggest that RU49 may play a critical role in their specification. Furthermore, these results raise the interesting possibility that the generation of these three neuronal populations to form displaced germinative zones within the developing brain may reflect their use of a common developmental mechanism involving RU49.
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Haldipur, P., I. Sivaprakasam, V. Periasamy, S. Govindan, and S. Mani. "Asymmetric cell division of granule neuron progenitors in the external granule layer of the mouse cerebellum." Biology Open 4, no. 7 (May 15, 2015): 865–72. http://dx.doi.org/10.1242/bio.009886.
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Mani, Shyamala, Saranya Radhakrishnan, Rajit Narayanan Cheramangalam, Shalini Harkar, Samyutha Rajendran, and Narendrakumar Ramanan. "Shh-Mediated Increase in β-Catenin Levels Maintains Cerebellar Granule Neuron Progenitors in Proliferation." Cerebellum 19, no. 5 (June 3, 2020): 645–64. http://dx.doi.org/10.1007/s12311-020-01138-2.
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Chatterjee, Anindo, Kaviya Chinnappa, Narendrakumar Ramanan, and Shyamala Mani. "Centrosome Inheritance Does Not Regulate Cell Fate in Granule Neuron Progenitors of the Developing Cerebellum." Cerebellum 17, no. 5 (April 16, 2018): 685–91. http://dx.doi.org/10.1007/s12311-018-0935-4.
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Ha, Seungshin, Prem P. Tripathi, Ray A. Daza, Robert F. Hevner, and David R. Beier. "Reelin Mediates Hippocampal Cajal-Retzius Cell Positioning and Infrapyramidal Blade Morphogenesis." Journal of Developmental Biology 8, no. 3 (September 18, 2020): 20. http://dx.doi.org/10.3390/jdb8030020.
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We have previously described hypomorphic reelin (Reln) mutant mice, RelnCTRdel, in which the morphology of the dentate gyrus is distinct from that seen in reeler mice. In the RelnCTRdel mutant, the infrapyramidal blade of the dentate gyrus fails to extend, while the suprapyramidal blade forms with a relatively compact granule neuron layer. Underlying this defect, we now report several developmental anomalies in the RelnCTRdel dentate gyrus. Most strikingly, the distribution of Cajal-Retzius cells was aberrant; Cajal-Retzius neurons were increased in the suprapyramidal blade, but were greatly reduced along the subpial surface of the prospective infrapyramidal blade. We also observed multiple abnormalities of the fimbriodentate junction. Firstly, progenitor cells were distributed abnormally; the “neurogenic cluster” at the fimbriodentate junction was absent, lacking the normal accumulation of Tbr2-positive intermediate progenitors. However, the number of dividing cells in the dentate gyrus was not generally decreased. Secondly, a defect of secondary glial scaffold formation, limited to the infrapyramidal blade, was observed. The densely radiating glial fibers characteristic of the normal fimbriodentate junction were absent in mutants. These fibers might be required for migration of progenitors, which may account for the failure of neurogenic cluster formation. These findings suggest the importance of the secondary scaffold and neurogenic cluster of the fimbriodentate junction in morphogenesis of the mammalian dentate gyrus. Our study provides direct genetic evidence showing that normal RELN function is required for Cajal-Retzius cell positioning in the dentate gyrus, and for formation of the fimbriodentate junction to promote infrapyramidal blade extension.
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Wu, Chuanqing, Mei Yang, Juan Li, Chengbing Wang, Ting Cao, Kaixiong Tao, and Baolin Wang. "Talpid3-Binding Centrosomal Protein Cep120 Is Required for Centriole Duplication and Proliferation of Cerebellar Granule Neuron Progenitors." PLoS ONE 9, no. 9 (September 24, 2014): e107943. http://dx.doi.org/10.1371/journal.pone.0107943.
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Yang, Haihong, Qian Zhu, Juanxian Cheng, Yan Wu, Ming Fan, Jiyan Zhang, and Haitao Wu. "Opposite regulation of Wnt/β-catenin and Shh signaling pathways by Rack1 controls mammalian cerebellar development." Proceedings of the National Academy of Sciences 116, no. 10 (February 14, 2019): 4661–70. http://dx.doi.org/10.1073/pnas.1813244116.
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The development of the cerebellum depends on intricate processes of neurogenesis, migration, and differentiation of neural stem cells (NSCs) and progenitor cells. Defective cerebellar development often results in motor dysfunctions and psychiatric disorders. Understanding the molecular mechanisms that underlie the complex development of the cerebellum will facilitate the development of novel treatment options. Here, we report that the receptor for activated C kinase (Rack1), a multifaceted signaling adaptor protein, regulates mammalian cerebellar development in a cell type-specific manner. Selective deletion of Rack1 in mouse NSCs or granule neuron progenitors (GNPs), but not Bergmann glial cells (BGs), causes severe defects in cerebellar morphogenesis, including impaired folia and fissure formation. NSCs and GNPs lacking Rack1 exhibit enhanced Wnt/β-catenin signaling but reduced Sonic hedgehog (Shh) signaling. Simultaneous deletion of β-catenin in NSCs, but not GNPs, significantly rescues theRack1mutant phenotype. Interestingly, Rack1 controls the activation of Shh signaling by regulating the ubiquitylation and stability of histone deacetylase 1 (HDAC1)/HDAC2. Suppression of HDAC1/HDAC2 activity in the developing cerebellum phenocopies theRack1mutant. Together, these results reveal a previously unknown role of Rack1 in controlling mammalian cerebellar development by opposite regulation of Wnt/β-catenin and Shh signaling pathways.
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Cleveland, Abigail, Katherine Veleta, and Timothy Gershon. "PDTM-05. SONIC HEDGEHOG SIGNALING PRIMES CEREBELLAR GRANULE NEURON PROGENITORS AND MEDULLOBLASTOMA CELLS FOR APOPTOSIS BY INDUCING PRO-APOPTOTIC BIM." Neuro-Oncology 21, Supplement_6 (November 2019): vi187—vi188. http://dx.doi.org/10.1093/neuonc/noz175.781.
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Abstract Medulloblastomas, unlike other malignant brain tumors, are typically sensitive to radiation therapy (xRT). However, although xRT allows medulloblastoma patients to survive, it can also confer significant long term cognitive sequelae. Understanding the mechanisms of radiation sensitivity in medulloblastoma may identify ways to increase this sensitivity through targeted therapy. Cerebellar granule neuron progenitors (CGNPs), the cells of origin for SHH-subgroup medulloblastoma, are also sensitive to xRT. We have shown that SHH signaling, which induces CGN proliferation and in excess can cause medulloblastoma, induces the pro-apoptotic protein BIM, resulting in increased radiation sensitivity. SHH-stimulated CGNPs show robust BIM expression, which is blocked by the SMO inhibitor vismodegib. CGNPs in BIM null mice show normal SHH-driven proliferation, but are markedly less sensitive to radiation. Protein studies show that BIM binds to the anti-apoptotic proteins BCL-xL and MCL-1, suggesting a mechanism for increasing the sensitivity to radiation by lowering the apoptotic threshold. On-going studies will determine whether BIM is required for radiation sensitivity in SHH-driven medulloblastoma. If validated, the BIM interactions with BCL-xL and MCL-1 may be novel mechanisms to be targeted to improve medulloblastoma therapy.
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Garcia-Lopez *, Jesus, Shiekh Tanveer Ahmad *, Yiran Li *, Brian Gudenas, Marija Kojic, Friedrik Manz, Barbara Jonchere, et al. "MEDB-42. GermlineElp1 deficiency promotes genomic instability and survival of granule neuron progenitors primed for SHH medulloblastoma pathogenesis." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i115. http://dx.doi.org/10.1093/neuonc/noac079.416.
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Abstract Germline loss-of-function (LOF) mutations in Elongator complex protein 1 (ELP1) are found in 15-20% of childhood SHH medulloblastoma (MB) and are exceedingly rare in non-SHH-MB or other cancers. ELP1 germline carriers that develop SHH-MB harbor frequent somatic PTCH1 mutations and universally sustain loss-of-heterozygosity of the remaining ELP1 allele through chromosome 9q deletion. ELP1 functions as a scaffolding subunit of the Elongator complex that is required for posttranscriptional modification of tRNAs and maintenance of efficient translational elongation and protein homeostasis. However, the molecular, biochemical, and cellular mechanisms by which ELP1/Elongator LOF contribute to SHH-MB tumorigenesis remain largely unknown. Herein, we report that mice harboring germline Elp1 monoallelic loss (i.e., Elp1+/-) exhibit hallmark features of malignant predisposition in developing cerebellar granule neuron progenitors (GNPs), the lineage-of-origin for SHH-MB. Elp1+/- GNPs are characterized by increased replication stress-induced DNA damage, upregulation of the homologous recombination repair pathway, aberrant cell cycle, and attenuation of p53-dependent apoptosis. CRISPR/Cas9-mediated Elp1 and Ptch1 gene targeting in mouse GNPs reproduces highly penetrant SHH-MB tumors recapitulating the molecular and phenotypic features of patient tumors. Reactivation of the p53 pathway through MDM2 and PAK4 inhibitors promotes selective cell death in patient-derived xenograft tumors (PDX) harboring deleterious ELP1 mutations. Together, our findings reveal that germline Elp1 deficiency heightens genomic instability and survival in GNPs, providing a mechanistic model for the subgroup-restricted pattern of predisposition and malignancy associated with pathogenic ELP1 germline carriers. These results provide rationale for further preclinical studies evaluating drugs that overcome p53 pathway inhibition in ELP1-associated SHH-MB and a renewed outlook for improving treatment options for affected children and their families.*, # Contributed equally
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Bihannic, L., A. Forget, S. M. Cigna, C. Lefevre, M. Remke, M. Barnat, S. Dodier, et al. "CS-01 * THE PHOSPHORYLATION OF ATOH1 LEADS TO ITS DEGRADATION MEDIATED BY THE E3 UBIQUITIN LIGASE HUWE1 IN GRANULE NEURON PROGENITORS." Neuro-Oncology 16, suppl 5 (November 1, 2014): v51. http://dx.doi.org/10.1093/neuonc/nou242.1.
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Garcia-Lopez, Jesus, Shiekh Tanveer Ahmad, Yiran Li, Brian Gudenas, Marija Kojic, Friedrik Manz, Barbara Jonchere, et al. "MDB-23. ELP1 GERMLINE DEFICIENCY SENSITIZES THE GRANULE NEURON LINEAGE TO SHH MEDULLOBLASTOMA AND EXPOSES NOVEL THERAPEUTIC VULNERABILITIES." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i67. http://dx.doi.org/10.1093/neuonc/noad073.255.
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Abstract Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB). ELP1 germline carriers develop SHH-MBs that exhibit coincident somatic PTCH1 mutations and universal loss-of-heterozygosity of the remaining ELP1 allele through chromosome 9q deletion. The molecular, biochemical, and cellular mechanisms by which germline ELP1/Elongator deficiency contribute to SHH-MB tumorigenesis remain largely unknown. Herein, we report that mice engineered to mimic germline Elp1 LOF (i.e., Elp1HET) seen in SHH-MB patients exhibit hallmark features of premalignancy events in cycling cerebellar granule neuron progenitors (GNPs), the lineage-of-origin for SHH-MB. Compared to wild-type counterparts, Elp1HET GNPs exhibit increased replication stress-associated DNA damage, homologous recombination-associated genomic instability, accelerated cell cycle kinetics, reduced p53-dependent apoptosis in response to genotoxic stress, and slowed differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation into the cerebella of immunocompromised mice promotes onset of SHH-MB tumors with incomplete penetrance that exhibit reduced p53 transcriptional activity through a currently unknown mechanism(s). Concomitant Elp1 and Ptch1 gene targeting in p53-null GNPs reproduces highly penetrant cerebellar tumors recapitulating the molecular and phenotypic features of ELP1-associated SHH-MB. Finally, reactivation of the p53 pathway through preclinical treatment with an MDM2 inhibitor promotes cell death and prolongs the survival of patient-derived xenograft tumor (PDX) models harboring deleterious ELP1 mutations. Together, our findings reveal that germline Elp1 LOF heightens genomic instability and malignant transformation in cycling GNPs, providing a mechanistic model for the subgroup-restricted pattern of predisposition associated with pathogenic ELP1 germline carriers. These results provide essential mechanistic insight into the molecular and cellular basis of SHH-MB predisposition driven by ELP1 LOF and nominate therapies that overcome p53 pathway inhibition as a rational treatment option for affected children.
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Forget, A., L. Bihannic, S. Cigna, C. Lefevre, M. Remke, M. Barnat, S. Dodier, et al. "CS-08 * SONIC HEDGEHOG SIGNALING PROTECTS ATOH1 FROM DEGRADATION MEDIATED BY THE HECT DOMAIN E3 UBIQUITIN LIGASE HUWE1 IN CEREBELLAR GRANULE NEURON PROGENITORS." Neuro-Oncology 16, suppl 5 (November 1, 2014): v52. http://dx.doi.org/10.1093/neuonc/nou242.8.
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Cleveland, Abigail, and Timothy Gershon. "MBRS-08. SONIC HEDGEHOG SIGNALING PRIMES CEREBELLAR GRANULE NEURON PROGENITORS, THE CELL OF ORIGIN FOR MEDULLOBLASTOMA, FOR APOPTOSIS BY INDUCING PRO APOPTOTIC BIM." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii400. http://dx.doi.org/10.1093/neuonc/noaa222.527.
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Abstract Medulloblastomas, unlike other malignant brain tumors, are typically sensitive to radiation therapy, but the mechanisms that mediate this sensitivity are unclear. Cerebellar granule neuron progenitors (CGNPs), the cell of origin for SHH-subgroup medulloblastoma, are also highly sensitive to radiation. In early life, CGNPs proliferate in response to Sonic Hedgehog (SHH) signaling, and hyperactivation of SHH signaling in CGNPs can lead to the development of SHH-subgroup medulloblastoma. We propose that SHH activation induces radiation sensitivity along with tumorigenesis. We have previously shown that the proapoptotic protein BAX is required for radiation sensitivity of both SHH-driven medulloblastomas and CGNPs in mice, and that BCL-xL supplies critical regulation of BAX, preventing spontaneous cell death. Here, we show that SHH signaling increases the radiation sensitivity of CGNPs by inducing the proapoptotic protein BIM. We found that BIM expression depends on SHH activity, and that genetic deletion of Bim decreases the radiation-sensitivity of CGNPs. Mechanistically, we show that BIM binds to anti-apoptotic proteins BCL-xL and MCL-1, where it may alter the balance of BAX and BCL-xL interactions. Consistent with our mechanistic model, human medulloblastoma patients with high BIM expression show a better prognosis. Based on these observations, we propose that SHH-induced BIM mediates the typical radiation sensitivity of SHH-driven medulloblastoma. Finding ways to enhance BIM activity may open new opportunities for targeted medulloblastoma therapy.
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Chang, Chia-Hsiang, Ting-Yu Chen, I.-Ling Lu, Rong-Bin Li, Jhih-Jie Tsai, Pin-Yeh Lin, and Tang K. Tang. "CEP120-mediated KIAA0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum." Genes & Development 35, no. 21-22 (October 28, 2021): 1445–60. http://dx.doi.org/10.1101/gad.348636.121.
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Joubert syndrome (JS) is a recessive ciliopathy in which all affected individuals have congenital cerebellar vermis hypoplasia. Here, we report that CEP120, a JS-associated protein involved in centriole biogenesis and cilia assembly, regulates timely neuronal differentiation and the departure of granule neuron progenitors (GNPs) from their germinal zone during cerebellar development. Our results show that depletion of Cep120 perturbs GNP cell cycle progression, resulting in a delay of cell cycle exit in vivo. To dissect the potential mechanism, we investigated the association between CEP120 interactome and the JS database and identified KIAA0753 (a JS-associated protein) as a CEP120-interacting protein. Surprisingly, we found that CEP120 recruits KIAA0753 to centrioles, and that loss of this interaction induces accumulation of GNPs in the germinal zone and impairs neuronal differentiation. Importantly, the replenishment of wild-type CEP120 rescues the above defects, whereas expression of JS-associated CEP120 mutants, which hinder KIAA0753 recruitment, does not. Together, our data reveal a close interplay between CEP120 and KIAA0753 for the germinal zone exit and timely neuronal differentiation of GNPs during cerebellar development, and mutations in CEP120 and KIAA0753 may participate in the heterotopia and cerebellar hypoplasia observed in JS patients.
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Tikunov, Andrey, Dale Bates, Jeff Macdonald, and Timothy Gershon. "TMET-01. DISRUPTION OF THE SERINE-PRODUCING PATHWAYS SLOWS PROGRESSION OF THE SONIC HEDGEHOG-DRIVEN MEDULLOBLASTOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii261. http://dx.doi.org/10.1093/neuonc/noac209.1006.
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Abstract We have found that medulloblastoma metabolism is specialized to promote growth in the CNS and can be targeted for anti-tumor therapy. Prior studies show that serine is scarce in the CNS and that metastatic tumors require serine-producing enzymes to grow in the brain. We analyzed whether medulloblastoma, a primary brain tumor, showed similar serine dependency. We found that Sonic Hedgehog signaling, which induces proliferation in cerebellar granule neuron progenitors in normal development and medulloblastoma formation when hyperactivated, also induces PHGDH and SHMT1, which each catalyze key steps in different serine-production pathways. To define the functional role of PHGDH and SHMT1 in medulloblastomas, we bred mice genetically engineered to develop SHH medulloblastomas with mice carrying deletions of each of these genes. We found that mice with Phgdh-deleted medulloblastomas showed slower progression and longer survival times, compared to mice with Phgdh-intact medulloblastomas. Medulloblastomas with combined deletion of Phgdh and Shmt1 show even slower tumor progression. Stable-isotope flux analysis suggests that different serine-producing pathways compensate for the loss of individual serine-producing enzymes, providing a rationale for the greater anti-tumor effect of disrupting multiple serine-producing enzymes simultaneously. Our data show that serine-producing enzymes can be targeted as a novel approach to medulloblastoma therapy, and underscore the importance of targeting multiple serine-production pathways in complex metabolic interventions.
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Dey, A., M. Robitaille, M. Remke, C. Maier, A. Malhotra, A. Gregorieff, J. Wrana, M. Taylor, S. Angers, and A. Kenney. "MB-02 * SONIC HEDGEHOG INDUCES YB-1 IN A YAP-DEPENDENT MANNER TO REGULATE Igf2 EXPRESSION AND PROLIFERATION IN CEREBELLAR GRANULE NEURON PROGENITORS AND MEDULLOBLASTOMA CELLS." Neuro-Oncology 17, suppl 3 (April 23, 2015): iii20. http://dx.doi.org/10.1093/neuonc/nov061.78.
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Shaik, Shavali, Shinji Maegawa, Ajay Sharma, Amanda Haltom, Tara Dobson, Yanwen Yang, Keri Schadler, and Vidya Gopalakrishnan. "TAMI-58. A NOVEL ROLE FOR REST IN THE CONTROL OF THE MEDULLOBLASTOMA MICROENVIRONMENT." Neuro-Oncology 22, Supplement_2 (November 2020): ii226. http://dx.doi.org/10.1093/neuonc/noaa215.945.
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Abstract The REI Silensing Transcription Factor (REST) is a transcriptional repressor and a canonical regulator of neurogenesis. Its expression is elevated in human sonic hedgehog (SHH) subgroup of medulloblastomas (MBs), where functional studies shown its elevated expression to promote proliferation and block neuronal specification. A role for REST in the control of the MB tumor microenvironment (TME) has not been described previously. Here, we demonstrate that REST also controls the MB-TME, and specifically vascular remodeling. Using our unique RESTTG mouse model, we show that conditional expression of human REST transgene in cerebellar granule neuron progenitors (CGNPs), the cell of origin of a subset of SHH MBs, promoted increased vascular growth. In the context of constitutive activation of SHH signaling, a key driver of SHH-MB development, REST elevation drove tumor progression by altering the tumor vasculature. These findings were validated in mouse orthotopic models of human MB cell lines and through analyses of publicly available transcriptomic database of human MB samples. A strong positive correlation between REST and that of endothelial genes CD31/VEGFR1/ETS1 was seen in samples from patients with SHH-MBs subtypes that are associated with the worst prognosis. Proteomic analyses identified increased secretion of a number of pro-angiogenic factors in the context of upregulated REST expression in MB cells. Unexpectedly, in vitro and in vivo studies showed that MB cells expressed these endothelial markers and co-localized with endothelial cells suggesting that REST elevation may have altered the fate of cells that were destined to become neurons. Finally, ETS1 knockdown in MB cell lines not only downregulated VEGFR1 levels in these cells, and blocked tube formation in vitro, but also caused a reduction in tumor cell co-localization with endothelial cells. Collectively, these data suggest that REST elevation remodels MB vasculature through cell-intrinsic and cell-extrinsic mechanisms.
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Lopez, Jesus Garcia, Lena Kutscher, Marija Kojic, Brian Gudenas, Kyle Smith, Jennifer Hadley, Amar Gajjar, et al. "MBRS-24. FUNCTIONAL CHARACTERIZATION OF IKBKAP/ELP1 AS A NOVEL SHH MEDULLOBLASTOMA PREDISPOSITION GENE." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii402—iii403. http://dx.doi.org/10.1093/neuonc/noaa222.540.
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Abstract Medulloblastoma (MB), a common malignant pediatric brain tumor, comprises at least four distinct molecular entities: WNT, SHH, Group 3, and Group 4. SHH-MB is driven by aberrant activation of the Sonic hedgehog (SHH) pathway in granule neuron progenitors (GNPs) and is associated with hereditary cancer predisposition syndromes including Li Fraumeni and Gorlin. We recently identified germline loss of function (LoF) mutations affecting IKBKAP/ELP1, the primary scaffolding subunit of the Elongator complex in a subset of SHH-MB patients. Germline ELP1 mutations account for ~15% of all pediatric SHH-MBs and position ELP1 as the most prevalent hereditary predisposition gene in MB. We genetically engineered Elp1 LoF in mouse GNPs to determine Elp1 function in cerebellar development and SHH-MB. Results of both mechanistic and phenotypic experiments demonstrate that GNPs harboring Elp1 loss exhibit ribosome pausing and protein aggregation, reinforcing the critical role of Elp1 in translational elongation and protein homeostasis. Further, we generated new transgenic mouse models mimicking germline ELP1 LoF mutations observed in SHH-MB patients. Elp1+/- transgenic mice exhibit purkinje cell degeneration and an increased DNA damage response. These mice are currently being evaluated for their capacity to recapitulate ELP1-associated SHH-MB. Additional analyses carried out on SHH-MB patient-derived xenografts showed that ELP1-mutant tumor cells specifically exhibit defects in tRNA biogenesis. Therefore, the function of ELP1 as a translational regulator is severely impaired in ELP1-mutant SHH-MBs. Our ongoing molecular and functional studies will provide important insights into the most common MB predisposition gene and will lay the foundation for future preclinical studies.
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Vouri, Mikaela, Audrey Mercier, Patricia Benites Goncalves da Silva, Konstantin Okonechnikov, Antoine Forget, Hua Yu, Anais Chivet, et al. "MBRS-51. MUTATIONS IN BRPF1 FOUND IN SHH MEDULLOBLASTOMA PREVENT INTERACTION WITH TP53 AND LEADS TO RADIORESISTANCE IN VITRO." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii406—iii407. http://dx.doi.org/10.1093/neuonc/noaa222.558.
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Abstract Medulloblastoma (MB) is one of the most common pediatric tumors in children. Among them, SHH subgroups of MB (MBSHH) is characterized by constitutive activation of SHH pathway. Somatic mutations in BRPF1, a chromatin modifier, is found in more than 5% of MBSHH and accounts for almost 20% of adult MBSHH but its potential role in MBSHH pathophysiology is still unknown. In this study, we first examined the function of Brpf1 on pro-tumorigenic features of MBSHH and evaluated molecular pathways regulated by Brpf1 using Brpf1floxed::Atoh1-Cre conditional knockout mice, in which Brpf1 is conditionally deleted in cerebellar granule neuron progenitors (GNPs). While RNA-seq analysis on GNPs from Brpf1 WT and KO mice showed significant differences in the pathways related with cell cycle and cell death, deletion of Brpf1 did not cause acceleration of tumorigenesis in the Ptch1 heterozygous tumor-prone. Background: Co-immunoprecipitation followed by mass spectrometry analysis identified interaction partners of BRPF1 including MOZ, MORF and ING5, known partners of BRPF1. Gene ontology analysis also depicted pathways important for cell cycle progression, cell death and response to DNA damage. Consistent with these observations, TP53 was identified as a novel co-factor of BRPF1. Of note, some of MBSHH-relevant BRPF1 mutations prevented interaction with TP53. According to the previous finding that cytosolic TP53 is required for apoptotic cell death, GNPs expressing the BRPF1-R600X mutant gene exhibited the resistance to irradiation-induced cell death. In conclusion, our data revealed that BRPF1 mutants found in MBSHH could prevent the complex formation with TP53, leading to enhanced resistance to cell apoptosis.
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Dobson, Tara H. W., Rong-Hua Tao, Jyothishmathi Swaminathan, Shinji Maegawa, Shavali Shaik, Javiera Bravo-Alegria, Ajay Sharma, et al. "Transcriptional repressor REST drives lineage stage–specific chromatin compaction atPtch1and increases AKT activation in a mouse model of medulloblastoma." Science Signaling 12, no. 565 (January 22, 2019): eaan8680. http://dx.doi.org/10.1126/scisignal.aan8680.
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In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH-α (children 3 to 16 years) and SHH-β (infants) subgroups. Neuronal maturation is greater in SHH-β than SHH-α tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model (RESTTG) wherein conditionalNeuroD2-controlledRESTtransgene expression in lineage-committedPtch1+/−cerebellar granule neuron progenitors (CGNPs) accelerated tumorigenesis and increased penetrance and infiltrative disease. This model revealed a neuronal maturation context–specific antagonistic interplay between the transcriptional repressor REST and the activator GLI1 atPtch1. Expression ofArrb1, which encodes β-arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committedRESTTGcells compared with wild-type proliferating CGNPs. Lineage-committedRESTTGcells also had decreased GLI1 activity and increased histone H3K9 methylation at thePtch1locus, which correlated with premature silencing ofPtch1. These cells also had decreased expression ofPten, which encodes a negative regulator of the kinase AKT. Expression ofPTCH1andGLI1were less, andARRB1was somewhat greater, in patient SHH-β than SHH-α MBs, whereas that ofPTENwas similarly lower in both subtypes than in others. Inhibition of histone modifiers or AKT reduced proliferation and induced apoptosis, respectively, in cultured REST-high MB cells. Our findings linking REST to differentiation-specific chromatin remodeling,PTCH1silencing, and AKT activation in MB tissues reveal potential subgroup-specific therapeutic targets for MB patients.
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Cleveland, Abigail, Katherine Veleta, and Timothy Gershon. "CBIO-23. ANTIAPOPTOTIC Bcl-xL RESTRICTS APOPTOSIS IN SHH MEDULLOBLASTOMA AND PROMOTES PROGRESSION." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi31—vi32. http://dx.doi.org/10.1093/neuonc/noab196.122.
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Abstract Medulloblastomas in most patients are distinctively sensitive to radiation therapy, but the mechanisms that mediate this sensitivity are unclear. Current treatments still fail 20%-60% of patients with SHH medulloblastoma and can leave survivors with long-term neurocognitive and social deficits. Understanding the mechanisms driving the typical radiation-sensitivity may identify less-toxic therapeutic strategies and provide insight into treatment failure. We previously showed that radiation sensitivity depends on the intrinsic apoptotic pathway, mediated by pro-apoptotic BAX. In cerebellar granule neuron progenitors (CGNPs), the cell of origin for SHH medulloblastoma, BAX activity is directly inhibited by anti-apoptotic BCL-xL; Bcl-xL-deleted CGNPs undergo spontaneous apoptosis. To test the therapeutic potential of disrupting BCL-xL in medulloblastoma, we conditionally deleted Bcl-xL in mice genetically engineered to develop SHH medulloblastoma. Here, I show that Bcl-xL deletion slows SHH medulloblastoma growth and prolongs survival of medulloblastoma-bearing mice. Bcl-xL-deleted tumors initially showed increased rates of spontaneous apoptosis, but this effect waned over time, suggesting the emergence of BCL-xL-independent survival mechanisms. We also noted increased microglial infiltration in Bcl-xL-deleted medulloblastomas. We hypothesize that IGF1 produced by microglia in the tumor microenvironment may be contributing to tumor resistance by upregulating translation of MCL-1, an anti-apoptotic BCL-xL homolog. IGF1 is known to upregulate translation through the mTOR pathway, while anti-apoptotic MCL-1 protein abundance is dependent upon translation regulation. Our on-going studies are testing the efficacy of pharmacologically targeting BCL-xL in mice with medulloblastoma, in combination with targeting IGF1 signaling using mTORC1 inhibitors.
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Cleveland, Abigail, Daniel Malawsky, Mehal Churiwal, and Timothy Gershon. "EMBR-15. PRC2 COMPLEX ENFORCES NEURONAL LINEAGE AND SUPPRESSES TUMOR GROWTH IN SHH MEDULLOBLASTOMA." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i8—i9. http://dx.doi.org/10.1093/neuonc/noab090.033.
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Abstract Hyperactivation of Sonic Hedgehog (SHH) signaling pathway drives tumor progression in the largest medulloblastoma subgroup. During cerebellar development, promoters of SHH target genes show inhibitory trimethylation of histone H3 at lysine 27 (H3K27me3), mediated by the Polycomb Repressive Complex 2 (PRC2). Here, we explored the regulation of cerebellar growth and medulloblastoma tumorigenesis by PRC2 complex components EED and EZH2. For developmental studies, we conditionally deleted Eed or Ezh2 in the Atoh1 lineage that gives rise to the cerebellar granule neuron progenitors (CGNP) that are cells of origin for SHH medulloblastomas. For tumor studies, we bred the conditional Eed- or Ezh2-deleted mouse lines with mice genetically engineered to develop SHH medulloblastoma. Our developmental studies showed that Eed was absolutely required for cerebellar growth. Eed-deleted CGNPs underwent aberrant, myocyte-like differentiation and spontaneous apoptosis, resulting in cerebellar hypoplasia. In contrast, Ezh2 deletion produced no developmental phenotype, despite blocking all H3K27me3 in CGNPs. Our tumor studies showed that Eed-deleted medulloblastomas similarly showed aberrant, myocyte differentiation, but unlike CGNPs, did not undergo widespread apoptosis. Eed-deleted medulloblastomas progressed more rapidly than control tumors, indicating that the inappropriate, muscle-like differentiation did not slow tumor growth. Ezh2-deleted medulloblastomas similarly progressed more rapidly than controls. Our data show that the PRC2 complex acts to enforce neuronal lineage commitment in both development and tumorigenesis and to restrain tumor growth in SHH medulloblastoma. Myocyte differentiation in Eed-deleted tumors suggests that PRC2 loss of function may contribute to the medullomyoblastomas that have been observed in patients. The differences in developmental phenotype show that EZH2 and EED functions are non-identical and can be dissociated, while similar increase in tumor progression show tumor suppressive functions for both EED and EZH2.
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Rosario, C. M., B. D. Yandava, B. Kosaras, D. Zurakowski, R. L. Sidman, and E. Y. Snyder. "Differentiation of engrafted multipotent neural progenitors towards replacement of missing granule neurons in meander tail cerebellum may help determine the locus of mutant gene action." Development 124, no. 21 (November 1, 1997): 4213–24. http://dx.doi.org/10.1242/dev.124.21.4213.
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Previously we observed that stable clones of multipotent neural progenitor cells, initially isolated and propagated from the external granular layer of newborn wild-type mouse cerebellum, could participate appropriately in cerebellar development when reimplanted into the external granular layer of normal mice. Donor cells could reintegrate and differentiate into neurons (including granule cells) and/or glia consistent with their site of engraftment. These findings suggested that progenitors might be useful for cellular replacement in models of aberrant neural development or neurodegeneration. We tested this hypothesis by implanting clonally related multipotent progenitors into the external granular layer of newborn meander tail mice (gene symbol=mea). mea is an autosomal recessive mutation characterized principally by the failure of granule cells to develop in the cerebellar anterior lobe; the mechanism is unknown. We report that approximately 75% of progenitors transplanted into the granuloprival anterior lobe of neonatal mea mutants differentiated into granule cells, partially replacing or augmenting that largely absent neuronal population in the internal granular layer of the mature meander tail anterior lobe. (The ostensibly ‘normal’ meander tail posterior lobe also benefited from repletion of a more subtle granule cell deficiency.) Donor-derived neurons were well-integrated within the neuropil, suggesting that these progenitors' developmental programs for granule cell differentiation were unperturbed. These observations permitted several conclusions. (1) That exogenous progenitors could survive transplantation into affected regions of neonatal meander tail cerebellum and differentiate into the deficient cell type suggested that the microenvironment was not inimical to granule cell development. Rather it suggested that mea's deleterious action is intrinsic to the external granular layer cell. (Any cell-extrinsic actions--albeit unlikely--had to be restricted to readily circumventable prenatal events.) This study, therefore, offers a paradigm for using progenitors to help determine the site of action of other mutant genes or to test hypotheses regarding the pathophysiology underlying other anomalies. (2) In the regions most deficient in neurons, a neuronal phenotype was pursued in preference to other potential cell types, suggesting a ‘push’ of undifferentiated, multipotent progenitors towards compensation for granule cell dearth. These data suggested that progenitors with the potential for multiple fates might differentiate towards repletion of deficient cell types, a possible developmental mechanism with therapeutic implications. Neural progenitors (donor or endogenous) might enable cell replacement in some developmental or degenerative diseases--most obviously in cases where a defect is intrinsic to the diseased cell, but also, under certain circumstances, when extrinsic pathologic forces may exist.
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Tsea, Ioanna, Yana Ruchiy, Manouk Verhoeven, Indranil Sinha, Klas Blomgren, Lena Maria Carlson, John Inge Johnsen, Cecilia Dyberg, and Ninib Baryawno. "Abstract 1677: Transcriptomic landscape of medulloblastoma reveals pathways of tumor-stroma remodelling." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1677. http://dx.doi.org/10.1158/1538-7445.am2022-1677.
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Abstract Medulloblastoma is one of the most common pediatric malignant brain tumors, currently comprising four distinct molecular subgroups: wingless [WNT], sonic hedgehog [SHH], and groups 3-4. Efforts to identify the mechanisms of medulloblastoma development have focused on mapping the extent of the tumor cell heterogeneity within each subgroup. Nevertheless, little is known about the role of the tumor microenvironment (TME) in medulloblastoma progression, particularly in subgroups 3-4, which have the worst prognosis due to metastatic disease. In this study, we performed single-cell transcriptomics on 14 human medulloblastoma samples spanning all molecular subgroups, to uncover novel TME-tumor interactions modulating medulloblastoma progression and metastasis. Unsupervised clustering of all medulloblastoma samples revealed 18 subclusters, including tumor granule neuron progenitors (GNPs) in different stages of differentiation, stromal cells (including oligodendrocyte precursors, mature oligodendrocytes, astrocytes, fibroblasts, endothelial cells and pericytes), myeloid cells (including microglia, monocytes and macrophages) as well as lymphoid cells. To investigate subgroup-specific signatures as well as TME-tumor pathways, we analyzed each subgroup separately. Analysis of supporting stroma cells in groups 3-4 demonstrated the presence of 8 different stroma populations, including a population of tumor-associated endothelial cells. Tumor-associated endothelial and fibroblast populations of groups 3-4 showed the highest expression of genes for vascular remodeling and extracellular matrix degradation, suggesting an active reprogramming of the stroma by tumor GNP cells to support medulloblastoma progression. Epithelial-to-mesenchymal transition-like processes that regulate stem cell, invasion and metastatic properties were upregulated in the tumor GNP populations of groups 3-4 compared to SHH and WNT subgroups. Finally, we highlight the presence of the CXCL1-CXCL5/CXCR2 metastasis-associated axis in groups 3-4 medulloblastomas as a potential therapeutic target. Our findings provide biological insights into TME processes for the different subgroups of medulloblastoma and possible new potential therapeutic avenues. Citation Format: Ioanna Tsea, Yana Ruchiy, Manouk Verhoeven, Indranil Sinha, Klas Blomgren, Lena Maria Carlson, John Inge Johnsen, Cecilia Dyberg, Ninib Baryawno. Transcriptomic landscape of medulloblastoma reveals pathways of tumor-stroma remodelling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1677.
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Zhang, Di, Xuezhen Wang, and Xin-Yun Lu. "Adiponectin Exerts Neurotrophic Effects on Dendritic Arborization, Spinogenesis, and Neurogenesis of the Dentate Gyrus of Male Mice." Endocrinology 157, no. 7 (May 17, 2016): 2853–69. http://dx.doi.org/10.1210/en.2015-2078.
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The hippocampus, a brain region critical for learning, memory and emotional processing, maintains its capacity to undergo structural plasticity throughout life. Hippocampal structural plasticity can be modulated by a number of intrinsic and extrinsic factors. This study investigated the effects of adiponectin, an adipocyte-derived hormone, on dendritic growth, arborization, and spinogenesis in mature granule neurons of the hippocampal dentate gyrus generated during embryonic (early-born) or early postnatal (late-born) stages. We found that adiponectin deficiency reduced dendritic length, branching and spine density of granule neurons. The reduction was more evident in early-born granule neurons than in late-born granule neurons. Intracerebroventricular infusion of adiponectin for 1 week increased of dendritic spines and arbor complexity in late-born granule neurons. Moreover, adiponectin deficiency decreased the production of adult-born new granule neurons through suppressing neural progenitor cell proliferation and differentiation, whereas intracerebroventricular adiponectin infusion increased the proliferation of neural progenitor cells in adult dentate gyrus. These results suggest that adiponectin plays an important role in dendritic spine remodeling and neurogenesis in the dentate gyrus.
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Jiang, Yifei, Dongyi Tong, Rylon D. Hofacer, Andreas W. Loepke, Qingquan Lian, and Steve C. Danzer. "Long-term Fate Mapping to Assess the Impact of Postnatal Isoflurane Exposure on Hippocampal Progenitor Cell Productivity." Anesthesiology 125, no. 6 (December 1, 2016): 1159–70. http://dx.doi.org/10.1097/aln.0000000000001358.
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Abstract Background Exposure to isoflurane increases apoptosis among postnatally generated hippocampal dentate granule cells. These neurons play important roles in cognition and behavior, so their permanent loss could explain deficits after surgical procedures. Methods To determine whether developmental anesthesia exposure leads to persistent deficits in granule cell numbers, a genetic fate-mapping approach to label a cohort of postnatally generated granule cells in Gli1-CreERT2::GFP bitransgenic mice was utilized. Green fluorescent protein (GFP) expression was induced on postnatal day 7 (P7) to fate map progenitor cells, and mice were exposed to 6 h of 1.5% isoflurane or room air 2 weeks later (P21). Brain structure was assessed immediately after anesthesia exposure (n = 7 controls and 8 anesthesia-treated mice) or after a 60-day recovery (n = 8 controls and 8 anesthesia-treated mice). A final group of C57BL/6 mice was exposed to isoflurane at P21 and examined using neurogenesis and cell death markers after a 14-day recovery (n = 10 controls and 16 anesthesia-treated mice). Results Isoflurane significantly increased apoptosis immediately after exposure, leading to cell death among 11% of GFP-labeled cells. Sixty days after isoflurane exposure, the number of GFP-expressing granule cells in treated animals was indistinguishable from control animals. Rates of neurogenesis were equivalent among groups at both 2 weeks and 2 months after treatment. Conclusions These findings suggest that the dentate gyrus can restore normal neuron numbers after a single, developmental exposure to isoflurane. The authors’ results do not preclude the possibility that the affected population may exhibit more subtle structural or functional deficits. Nonetheless, the dentate appears to exhibit greater resiliency relative to nonneurogenic brain regions, which exhibit permanent neuron loss after isoflurane exposure.
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Lattanzi, Davide, David Savelli, Marica Pagliarini, Riccardo Cuppini, and Patrizia Ambrogini. "Short-Term, Voluntary Exercise Affects Morpho-Functional Maturation of Adult-Generated Neurons in Rat Hippocampus." International Journal of Molecular Sciences 23, no. 12 (June 20, 2022): 6866. http://dx.doi.org/10.3390/ijms23126866.
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Physical exercise is a well-proven neurogenic stimulus, promoting neuronal progenitor proliferation and affecting newborn cell survival. Besides, it has beneficial effects on brain health and cognition. Previously, we found that three days of physical activity in a very precocious period of adult-generated granule cell life is able to antedate the appearance of the first GABAergic synaptic contacts and increase T-type Ca2+ channel expression. Considering the role of GABA and Ca2+ in fostering neuronal maturation, in this study, we used short-term, voluntary exercise on a running wheel to investigate if it is able to induce long-term morphological and synaptic changes in newborn neurons. Using adult male rats, we found that: (i) three days of voluntary physical exercise can definitively influence the morpho-functional maturation process of newborn granule neurons when applied very early during their development; (ii) a significant percentage of new neurons show more mature morphological characteristics far from the end of exercise protocol; (iii) the long-term morphological effects result in enhanced synaptic plasticity. Present findings demonstrate that the morpho-functional changes induced by exercise on very immature adult-generated neurons are permanent, affecting the neuron maturation and integration in hippocampal circuitry. Our data contribute to underpinning the beneficial potential of physical activity on brain health, also performed for short times.
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Alcantara, S., M. Ruiz, F. De Castro, E. Soriano, and C. Sotelo. "Netrin 1 acts as an attractive or as a repulsive cue for distinct migrating neurons during the development of the cerebellar system." Development 127, no. 7 (April 1, 2000): 1359–72. http://dx.doi.org/10.1242/dev.127.7.1359.
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Netrin 1 is a long-range diffusible factor that exerts chemoattractive or chemorepulsive effects on developing axons growing to or away from the neural midline. Here we used tissue explants to study the action of netrin 1 in the migration of several cerebellar and precerebellar cell progenitors. We show that netrin 1 exerts a strong chemoattractive effect on migrating neurons from the embryonic lower rhombic lip at E12-E14, which give rise to precerebellar nuclei. Netrin 1 promotes the exit of postmitotic migrating neurons from the embryonic lower rhombic lip and upregulates the expression of TAG-1 in these neurons. In addition, in the presence of netrin 1, the migrating neurons are not isolated but are associated with thick fascicles of neurites, typical of the neurophilic way of migration. In contrast, the embryonic upper rhombic lip, which contains tangentially migrating granule cell progenitors, did not respond to netrin 1. Finally, in the postnatal cerebellum, netrin 1 repels both the parallel fibres and migrating granule cells growing out from explants taken from the external germinal layer. The developmental patterns of expression in vivo of netrin 1 and its receptors are consistent with the notion that netrin 1 secreted in the midline acts as chemoattractive cue for precerebellar neurons migrating circumferentially along the extramural stream. Similarly, the pattern of expression in the postnatal cerebellum suggests that netrin 1 could regulate the tangential migration of postmitotic premigratory granule cells. Thus, molecular mechanisms considered as primarily involved in axonal guidance appear also to steer neuronal cell migration.
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Ayad, Nagi. "GENE-44. BRD4 DELETION LEADS TO CEREBELLAR DEFICITS AND ATAXIA." Neuro-Oncology 21, Supplement_6 (November 2019): vi107. http://dx.doi.org/10.1093/neuonc/noz175.446.
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Abstract Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications.
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Lee, H. Y., J. M. Angelastro, A. M. Kenney, C. Mason, and L. Greene. "[P1.16]: Regulation of ATF5 during cerebellar granule neuron progenitor proliferation and differentiation." International Journal of Developmental Neuroscience 26, no. 8 (November 25, 2008): 847. http://dx.doi.org/10.1016/j.ijdevneu.2008.09.066.
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Tiberi, Luca. "PDTM-35. MODELLING MEDULLOBLASTOMA WITH MOUSE MODELS AND HUMAN CEREBELLAR ORGANOIDS." Neuro-Oncology 21, Supplement_6 (November 2019): vi195. http://dx.doi.org/10.1093/neuonc/noz175.811.
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Abstract Malignant medulloblastoma (MB) is the most common brain tumor affecting children and it remains responsible for a high percentage of morbidity and mortality among cancer patients. During the past few years, studies on human MB and mouse models have uncovered the existence of four major MB groups, with specific pathological and molecular features: WNT, SHH, Group 3 and Group 4. Of the four groups, patients with Group 3 MB have the worst outcome with nearly 50% of the tumors metastatic at the time of diagnosis. Therefore, developing “humanized “ mouse model of Group3 Medulloblastoma would be of paramount importance for the identification and testing of new drugs for pediatric patients, tailored on the genetic condition of the patient itself. We performed an in-vivo screen to identify new cancer-inducing genes starting from the published genome-wide analyses of MB patients. This screen led to the identification of novel driver gene combinations required for tumorigenesis. To study Medulloblastoma in human cells, we generated human cerebellar organoids. Organoids are cellular structures that resemble whole organs and can be generated from pluripotent stem cells or isolated organ progenitors. We were able to induce cerebellar progenitors to self-form neuro-epithelial structures that mimic early human cerebellar plate, composed by cerebellar progenitors, cerebellar neurons (interneurons, Purkinje cells, and granule neurons) and glial cells. Notably, we have generated human putative iPSC-derived cancer organoids with gene combinations mimicking human Group3 MB. Indeed, organoids that mimic cancer can be used as an alternative system for drug testing that better recapitulate effects in human patients as compared to other in-vitro and in-vivo systems.
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Anne, Sandrine L., Eve-Ellen Govek, Olivier Ayrault, Jee Hae Kim, Xiaodong Zhu, David A. Murphy, Linda Van Aelst, Martine F. Roussel, and Mary E. Hatten. "WNT3 Inhibits Cerebellar Granule Neuron Progenitor Proliferation and Medulloblastoma Formation via MAPK Activation." PLoS ONE 8, no. 11 (November 26, 2013): e81769. http://dx.doi.org/10.1371/journal.pone.0081769.
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Stoyanova, Irina, Andrii Klymenko, Jeannette Willms, Thorsten Doeppner, Anton Tonchev, and David Lutz. "Ghrelin Regulates Expression of the Transcription Factor Pax6 in Hypoxic Brain Progenitor Cells and Neurons." Cells 11, no. 5 (February 23, 2022): 782. http://dx.doi.org/10.3390/cells11050782.
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The nature of brain impairment after hypoxia is complex and recovery harnesses different mechanisms, including neuroprotection and neurogenesis. Experimental evidence suggests that hypoxia may trigger neurogenesis postnatally by influencing the expression of a variety of transcription factors. However, the existing data are controversial. As a proof-of-principle, we subjected cultured cerebral cortex neurons, cerebellar granule neurons and organotypic cerebral cortex slices from rat brains to hypoxia and treated these cultures with the hormone ghrelin, which is well-known for its neuroprotective functions. We found that hypoxia elevated the expression levels and stimulated nuclear translocation of ghrelin’s receptor GHSR1 in the cultured neurons and the acute organotypic slices, whereas ghrelin treatment reduced the receptor expression to normoxic levels. GHSR1 expression was also increased in cerebral cortex neurons of mice with induced experimental stroke. Additional quantitative analyses of immunostainings for neuronal proliferation and differentiation markers revealed that hypoxia stimulated the proliferation of neuronal progenitors, whereas ghrelin application during the phase of recovery from hypoxia counteracted these effects. At the mechanistic level, we provide a link between the described post-ischemic phenomena and the expression of the transcription factor Pax6, an important regulator of neural progenitor cell fate. In contrast to the neurogenic niches in the brain where hypoxia is known to increase Pax6 expression, the levels of the transcription factor in cultured hypoxic cerebral cortex cells were downregulated. Moreover, the application of ghrelin to hypoxic neurons normalised the expression levels of these factors. Our findings suggest that ghrelin stimulates neurogenic factors for the protection of neurons in a GHSR1-dependent manner in non-neurogenic brain areas such as the cerebral cortex after exposure to hypoxia.
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Chang, Chia-Hsiang, Marco Zanini, Hamasseh Shirvani, Jia-Shing Cheng, Hua Yu, Chih-Hsin Feng, Audrey L. Mercier, et al. "Atoh1 Controls Primary Cilia Formation to Allow for SHH-Triggered Granule Neuron Progenitor Proliferation." Developmental Cell 48, no. 2 (January 2019): 184–99. http://dx.doi.org/10.1016/j.devcel.2018.12.017.
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Lee, Hae Young, James M. Angelastro, Anna Marie Kenney, Carol A. Mason, and Lloyd A. Greene. "Reciprocal actions of ATF5 and Shh in proliferation of cerebellar granule neuron progenitor cells." Developmental Neurobiology 72, no. 6 (May 14, 2012): 789–804. http://dx.doi.org/10.1002/dneu.20979.
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Sharma, Geeta. "The dominant functional nicotinic receptor in progenitor cells in the rostral migratory stream is the α3β4 subtype." Journal of Neurophysiology 109, no. 3 (February 1, 2013): 867–72. http://dx.doi.org/10.1152/jn.00886.2012.
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Addition of newly generated neurons into mature neural circuits in the adult CNS responds to changes in neurotransmitter levels and is tightly coupled to the activity of specific brain regions. This postnatal neurogenesis contributes to plasticity of the olfactory bulb and hippocampus and is thought to play a role in learning and memory, context and odor discrimination, as well as perceptual learning. While acetylcholine plays an important role in odor discrimination and perceptual learning, its role in adult neurogenesis in the olfactory bulb has not been elucidated. In this study, I have examined the functional expression of nAChRs in progenitor cells of the rostral migratory stream (RMS) in the adult olfactory bulb of mice. I show that most of these cells in the RMS exhibit large nAChR-mediated calcium transients upon application of acetylcholine (ACh). Unlike in the hippocampus, the predominant functional nAChRs on progenitor cells are of α3β4 subtype. Interestingly, functional receptor expression is lost once progenitor cells mature, and are incorporated into the granule cell layer. Instead, nAChRs are now expressed on some presynaptic terminals and modulate glutamate release onto granule cells. My results imply that ACh is a part of the permissive niche and likely plays a role in development of progenitor cells.
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Wang, Wei, Qiang Qu, Frances I. Smith, and Daniel L. Kilpatrick. "Self-inactivating lentiviruses: Versatile vectors for quantitative transduction of cerebellar granule neurons and their progenitors." Journal of Neuroscience Methods 149, no. 2 (December 2005): 144–53. http://dx.doi.org/10.1016/j.jneumeth.2005.05.019.
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Przyborski, S. A., B. B. Knowles, and S. L. Ackerman. "Embryonic phenotype of Unc5h3 mutant mice suggests chemorepulsion during the formation of the rostral cerebellar boundary." Development 125, no. 1 (January 1, 1998): 41–50. http://dx.doi.org/10.1242/dev.125.1.41.
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Mutation of the Unc5h3 (formally known as rcm) gene has important consequences on neuronal migration during cerebellar development. Unc5h3 transcripts are expressed early (embryonic day 8.5) in the hindbrain region and later in the cerebellar primordia. In Unc5h3 mutant embryos, both the development and initial migration of Purkinje cell progenitors occur as in wild-type controls. The rhombic lip, from which granule cell precursors arise, also appears to form normally in mutants. However, at E13.5, an abnormal subpopulation of granule cell and Purkinje cell precursors becomes detectable in rostral areas of the Unc5h3 mutant brain stem. These ectopic cerebellar cells increase in number and continue moving in a rostral direction throughout the remainder of embryogenesis and early stages of postnatal development invading the lateral regions of the pontine area and eventually the inferior colliculus. Cell proliferation markers demonstrate the mitotic nature of these subpial ectopic granule neurons indicating the displacement of the rostral external germinal layer in mutant animals. Our data suggest that establishment of the rostral cerebellar boundary may rely on chemorepulsive signaling events that require UNC5H3 expressed by cerebellar neurons and extracellular ligands that are functionally related to the UNC5H3-binding, guidance molecule netrin1. Although the phenotype resulting from the Unc5h3 mutation is apparently limited to the formation of the cerebellum, additional sites of Unc5h3 expression are also found during development suggesting the compensatory function of other genes.
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Zigova, Tanja, Viorica Pencea, Ranjita Betarbet, Stanley J. Wiegand, Charlie Alexander, Roy A. E. Bakay, and Marla B. Luskin. "Neuronal Progenitor Cells of the Neonatal Subventricular Zone Differentiate and Disperse following Transplantation into the Adult Rat Striatum." Cell Transplantation 7, no. 2 (March 1998): 137–56. http://dx.doi.org/10.1177/096368979800700209.
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We have investigated the suitability of a recently identified and characterized population of neuronal progenitor cells for their potential use in the replacement of degenerating or damaged neurons in the mammalian brain. The unique population of neuronal progenitor cells is situated in a well-delineated region of the anterior part of the neonatal subventricular zone (referred to as SVZa). This region can be separated from the remaining proliferative, gliogenic, subventricular zone encircling the lateral ventricles of the forebrain. Because the neurons arising from the highly enriched neurogenic progenitor cell population of the SVZa ordinarily migrate considerable distances and ultimately express the neurotransmitters GABA and dopamine, we have examined whether they could serve as an alternative source of tissue for neural transplantation. SVZa cells from postnatal day 0-2 rats, prelabeled by intraperitoneal injections of the cell proliferation marker BrdU, were implanted into the striatum of adult rats approximately 1 mo after unilateral denervation by 6-OHDA. To examine the spatio-temporal distribution and phenotype of the transplanted SVZa cells, the experimental recipients were perfused at short (less than 1 wk), intermediate (2-3 wk) and long (5 mo) postimplantation times. The host brains were sectioned and stained with an antibody to BrdU and one of several cell-type specific markers to determine the phenotypic characteristics of the transplanted SVZa cells. To identify neurons we used the neuron-specific antibody TuJ1, or antimembrane-associated protein 2 (MAP-2), and anti-GFAP was used to identify astrocytic glia. At all studied intervals the majority of the surviving SVZa cells exhibited a neuronal phenotype. Moreover, morphologically they could be distinguished from the cells of the host striatum because they resembled the intrinsic granule cells of the olfactory bulb, their usual fate. At longer times, a greater number of the transplanted SVZa cells had migrated from their site of implantation, often towards an outlying blood vessel, and the density of cells within the core of the transplant was reduced. Furthermore, there were rarely signs of transplant rejection or a glial scar surrounding the transplant. In the core of the transplant there were low numbers of GFAP-positive cells, indicating that the transplanted SVZa cells, predominantly TuJ1-positive/MAP2-positive, express a neuronal phenotype. Collectively, the propensity of the SVZa cells to express a neuronal phenotype and to survive and integrate in the striatal environment suggest that they may be useful in the reconstruction of the brain following CNS injury or disease.
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Alder, Janet, Kevin J. Lee, Thomas M. Jessell, and Mary E. Hatten. "Generation of cerebellar granule neurons in vivo by transplantation of BMP-treated neural progenitor cells." Nature Neuroscience 2, no. 6 (June 1999): 535–40. http://dx.doi.org/10.1038/9189.
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Sun, Gerald J., Yi Zhou, Ryan P. Stadel, Jonathan Moss, Jing Hui A. Yong, Shiori Ito, Nicholas K. Kawasaki, et al. "Tangential migration of neuronal precursors of glutamatergic neurons in the adult mammalian brain." Proceedings of the National Academy of Sciences 112, no. 30 (July 13, 2015): 9484–89. http://dx.doi.org/10.1073/pnas.1508545112.
Full textAbstract:
In a classic model of mammalian brain formation, precursors of principal glutamatergic neurons migrate radially along radial glia fibers whereas GABAergic interneuron precursors migrate tangentially. These migration modes have significant implications for brain function. Here we used clonal lineage tracing of active radial glia-like neural stem cells in the adult mouse dentate gyrus and made the surprising discovery that proliferating neuronal precursors of glutamatergic granule neurons exhibit significant tangential migration along blood vessels, followed by limited radial migration. Genetic birthdating and morphological and molecular analyses pinpointed the neuroblast stage as the main developmental window when tangential migration occurs. We also developed a partial “whole-mount” dentate gyrus preparation and observed a dense plexus of capillaries, with which only neuroblasts, among the entire population of progenitors, are directly associated. Together, these results provide insight into neuronal migration in the adult mammalian nervous system.
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Wang, Lin, Jangham Jung, Husam Babikir, Karin Shamardani, Noriyuki Kasahara, Sabine Müller, and Aaron Diaz. "MEDB-59. A draft atlas of medulloblastoma cellular evolution under therapy." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i120. http://dx.doi.org/10.1093/neuonc/noac079.433.
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Abstract How standard care shapes the cellular composition of recurrent medulloblastoma (MB), if therapy selects for specific tumor or immune cell types, is unknown. We report the pilot phase of our ongoing effort to profile human longitudinal MB specimens via single-cell transcriptomics and epigenetics. We profiled 11 diagnostic and eight recurrent specimens from 19 subjects via single-nucleus RNA sequencing (snRNA-seq), and four subjects via single-nucleus assay for transposase-accessible chromatin. Specimens from select subjects were also profiled to assess genome-wide enhancer activity via single-nucleus cleavage-under-targets and tagmentation. We found an upregulation of the DNA-damage response, RNA translation, WNT and NOTCH signaling in recurrent specimens. The percentages of stem-like cells increased by over two-fold at recurrence. We found that microglia and oligodendrocyte-lineage cells were the most abundant non-malignant tumor-associated cell types, representing 2%-10% of cells profiled. Microglia abundances were relatively stable across molecular subtypes, and when comparing primary to recurrent tumors. There was a moderate, but statistically significant, increase in oligodendrocyte abundance in SSH and WNT tumors, compared to Group 3/4 tumors. We compared gene expression in tumor cells with public snRNA-seq from developing human cerebella (PCW 9-21). Combined Group-3/4 cell analysis supports a common lineage hierarchy, with an enrichment for unipolar brush-cell and Purkinje-cell phenotypes found in Group-4 tumors. All Group-3/4 cases contained cycling cells expressing markers of PAX2+ interneuron progenitors, most cycling cells had this phenotype. All specimens contained populations of non-cycling granule-cell progenitor-like cells. We performed single-cell co-expression receptor/ligand analysis to infer paracrine signaling between tumor and non-malignant cell types. This identified both tumor cells and microglia as sources of growth factors, pro-inflammatory cytokines, and pro-apoptotic ligands. Non-malignant oligodendrocyte-lineage cells uniquely expressed IL6-family cytokines, pleiotrophin, and class-III semaphorins. These studies shed light on the cellular heterogeneity of MB and the effect of standard therapy in shaping composition at recurrence.
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Hattori, Noriko, Shozo Ohta, Takashi Sakamoto, Satoshi Mishima, and Shoei Furukawa. "Royal Jelly Facilitates Restoration of the Cognitive Ability in Trimethyltin-Intoxicated Mice." Evidence-Based Complementary and Alternative Medicine 2011 (2011): 1–6. http://dx.doi.org/10.1093/ecam/nep029.
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Trimethyltin (TMT) is a toxic organotin compound that induces acute neuronal death selectively in the hippocampal dentate gyrus (DG) followed by cognition impairment; however the TMT-injured hippocampal DG itself is reported to regenerate the neuronal cell layer through rapid enhancement of neurogenesis. Neural stem/progenitor cells (NS/NPCs) are present in the adult hippocampal DG, and generate neurons that can function for the cognition ability. Therefore, we investigated whether royal jelly (RJ) stimulates the regenerating processes of the TMT-injured hippocampal DG, and found that orally administered RJ significantly increased the number of DG granule cells and simultaneously improved the cognitive impairment. Furthermore, we have already shown that RJ facilitates neurogenesis of cultured NS/NPCs. These present results, taken together with previous observations, suggest that the orally administered RJ may be a promising avenue for ameliorating neuronal function by regenerating hippocampal granule cells that function in the cognition process.
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Sarnat, Harvey B. "8. Maturation of the Fetal Olfactory Bulb." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 42, S2 (August 2015): S4. http://dx.doi.org/10.1017/cjn.2015.256.
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The olfactory bulb exhibits architecture unique amongst laminar cortices, lacking molecular and subplate zones and having superficial synaptic glomeruli. Its ontogenesis also is unique because neuroblasts do not migrate radially but stream in from the rostral telencephalon; an ependymal-lined olfactory ventricle is transitory. The olfactory is the only sensory system to not project to the thalamus but incorporates a thalamic equivalent. It is a repository of progenitor cells in the mature brain. The aim was to define olfactory bulb development in the human foetus: synaptogenesis and cellular maturation.Immunoreactivity in paraffin sections of synaptophysin, NeuN, calretinin, vimentin and nestin was examined at autopsy in olfactory bulb in 20 foetuses, 9-40wks gestation. Synaptophysin reactivity was seen around the somata of mitral and tufted neurons at 9wks, synaptic glomeruli at 13wks. The granule cell layer in the core exhibited NeuN-reactive nuclei in cells of the outer half at 20wks; 60% of granular neurons reacted by term. Synaptophysin reactivity in the granular layer initiates at 15wk. GABAergic calretinin-reactive neurons and neurites and synaptic glomeruli appeared at 13wks. Nestin- and vimentin-reactive bipolar progenitor cells were shown at all gestational ages, mainly in the granular layer, the ratio to other cells remaining constant. Synapses form in the small accessory olfactory bulb of the nervus terminalis earlier than in the main bulb. Development of synaptic vesicles in the human fetal olfactory bulb is precise both spatially and temporally, but not yet fully mature at term.In brain malformations and congenital metabolic and genetic diseases, the olfactory bulb may be affected and provide additional neuropathological data. Therapeutic autologous transplantation of olfactory progenitor cells focus renewed interest in the olfactory bulb.
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Kamiya, Shiori, Tetsuya Kobayashi, and Kazuhiko Sawada. "Tracking of Internal Granular Progenitors Responding to Valproic Acid in the Cerebellar Cortex of Infant Ferrets." Cells 13, no. 4 (February 7, 2024): 308. http://dx.doi.org/10.3390/cells13040308.
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Internal granular progenitors (IGPs) in the developing cerebellar cortex of ferrets differentiate towards neural and glial lineages. The present study tracked IGPs that proliferated in response to valproic acid (VPA) to determine their fate during cerebellar cortical histogenesis. Ferret kits were used to administer VPA (200 μg/g body weight) on postnatal days 6 and 7. EdU and BrdU were injected on postnatal days 5 and 7, respectively, to label the post-proliferative and proliferating cells when exposed to VPA. At postnatal day 20, when the external granule layer was most expanded, EdU- and BrdU-single-labeled cells were significantly denser in the inner granular layer of VPA-exposed ferrets than in controls. No EdU- or BrdU-labeling was found in Purkinje cells and molecular layer interneurons. Significantly higher percentages of NeuN and Pax6 immunostaining in VPA-exposed ferrets revealed VPA-induced differentiation of IGPs towards granular neurons in BrdU-single-labeled cells. In contrast, both EdU- and BrdU-single-labeled cells exhibited significantly greater percentages of PCNA immunostaining, which appeared in immature Bergman glia, in the internal granular layer of VPA-exposed ferrets. These findings suggest that VPA affects the proliferation of IGPs to induce differentiative division towards granular neurons as well as post-proliferative IGPs toward differentiation into Bergmann glia.