Journal articles: 'Mesothelioma, primary cilium, hedgehog pathway'

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Barbarino, Marcella, Maria Bottaro, Laura Spagnoletti, Maria Margherita de de Santi, Raffaella Guazzo, Chiara Defraia, Cosimo Custoza, et al. "Analysis of Primary Cilium Expression and Hedgehog Pathway Activation in Mesothelioma Throws Back Its Complex Biology." Cancers 14, no. 21 (October 25, 2022): 5216. http://dx.doi.org/10.3390/cancers14215216.

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The primary cilium (PC) is a sensory organelle present on the cell surface, modulating the activity of many pathways. Dysfunctions in the PC lead to different pathologic conditions including cancer. Hedgehog signaling (Hh) is regulated by PC and the loss of its control has been observed in many cancers, including mesothelioma. Malignant pleural mesothelioma (MPM) is a fatal cancer of the pleural membranes with poor therapeutic options. Recently, overexpression of the Hh transcriptional activator GL1 has been demonstrated to be associated with poor overall survival (OS) in MPM. However, unlike other cancers, the response to G-protein-coupled receptor smoothened (SMO)/Hh inhibitors is poor, mainly attributable to the lack of markers for patient stratification. For all these reasons, and in particular for the role of PC in the regulation of Hh, we investigated for the first time the status of PC in MPM tissues, demonstrating intra- and inter-heterogeneity in its expression. We also correlated the presence of PC with the activation of the Hh pathway, providing uncovered evidence of a PC-independent regulation of the Hh signaling in MPM. Our study contributes to the understanding MPM heterogeneity, thus helping to identify patients who might benefit from Hh inhibitors.

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Ma, Ming, Emilie Legué, Xin Tian, Stefan Somlo, and Karel F. Liem. "Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease." Journal of the American Society of Nephrology 30, no. 11 (August 26, 2019): 2103–11. http://dx.doi.org/10.1681/asn.2018121274.

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BackgroundPKD1 or PKD2, the two main causal genes for autosomal dominant polycystic kidney disease (ADPKD), encode the multipass transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Polycystins localize to the primary cilium, an organelle essential for cell signaling, including signal transduction of the Hedgehog pathway. Mutations in ciliary genes that build and maintain the cilium also cause renal cystic disease through unknown pathways. Although recent studies have found alterations in Hedgehog signaling in ADPKD-related models and tissues, the relationship between Hedgehog and polycystic kidney disease is not known.MethodsTo examine the potential role of cell-autonomous Hedgehog signaling in regulating kidney cyst formation in vivo in both early- and adult-onset mouse models of ADPKD, we used conditional inactivation of Pkd1 combined with conditional modulation of Hedgehog signaling components in renal epithelial cells, where mutations in Pkd1 initiate cyst formation. After increasing or decreasing levels of Hedgehog signaling in cells that underwent inactivation of Pkd1, we evaluated the effects of these genetic manipulations on quantitative parameters of polycystic kidney disease severity.ResultsWe found that in Pkd1 conditional mutant mouse kidneys, neither downregulation nor activation of the Hedgehog pathway in epithelial cells along the nephron significantly influenced the severity of the polycystic kidney phenotype in mouse models of developmental or adult-onset of ADPKD.ConclusionsThese data suggest that loss of Pkd1 function results in kidney cysts through pathways that are not affected by the activity of the Hedgehog pathway.

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Gómez, Arianna Ericka, Angela K. Christman, Julie Craft Van De Weghe, Malaney Finn, and Dan Doherty. "Systematic analysis of cilia characteristics and Hedgehog signaling in five immortal cell lines." PLOS ONE 17, no. 12 (December 29, 2022): e0266433. http://dx.doi.org/10.1371/journal.pone.0266433.

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Dysfunction of the primary cilium, a microtubule-based signaling organelle, leads to genetic conditions called ciliopathies. Hedgehog (Hh) signaling is mediated by the primary cilium in vertebrates and is therefore implicated in ciliopathies; however, it is not clear which immortal cell lines are the most appropriate for modeling pathway response in human disease; therefore, we systematically evaluated Hh in five commercially available, immortal mammalian cell lines: ARPE-19, HEK293T, hTERT RPE-1, NIH/3T3, and SH-SY5Y. Under proper conditions, all of the cell lines ciliated adequately for our subsequent experiments, except for SH-SY5Y which were excluded from further analysis. hTERT RPE-1 and NIH/3T3 cells relocalized Hh pathway components Smoothened (SMO) and GPR161 and upregulated Hh target genes in response to pathway stimulation. In contrast, pathway stimulation did not induce target gene expression in ARPE-19 and HEK293T cells, despite SMO and GPR161 relocalization. These data indicate that human hTERT RPE-1 cells and murine NIH/3T3 cells, but not ARPE-19 and HEK293T cells, are suitable for modeling the role of Hh signaling in ciliopathies.

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Jung, Bomi, Daniela Padula, Ingo Burtscher, Cedric Landerer, Dominik Lutter, Fabian Theis, Ana C. Messias, et al. "Pitchfork and Gprasp2 Target Smoothened to the Primary Cilium for Hedgehog Pathway Activation." PLOS ONE 11, no. 2 (February 22, 2016): e0149477. http://dx.doi.org/10.1371/journal.pone.0149477.

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Zhang, Boyan, Tenghan Zhuang, Qiaoyu Lin, Biying Yang, Xiaowei Xu, Guangwei Xin, Shicong Zhu, et al. "Patched1–ArhGAP36–PKA–Inversin axis determines the ciliary translocation of Smoothened for Sonic Hedgehog pathway activation." Proceedings of the National Academy of Sciences 116, no. 3 (December 31, 2018): 874–79. http://dx.doi.org/10.1073/pnas.1804042116.

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The Sonic Hedgehog (Shh) pathway conducts primarily in the primary cilium and plays important roles in cell proliferation, individual development, and tumorigenesis. Shh ligand binding with its ciliary membrane-localized transmembrane receptor Patched1 results in the removal of Patched1 from and the translocation of the transmembrane oncoprotein Smoothened into the cilium, leading to Shh signaling activation. However, how these processes are coupled remains unknown. Here, we show that the Patched1–ArhGAP36–PKA–Inversin axis determines the ciliary translocation of Smoothened. We find that Patched1 interacts with and stabilizes the PKA negative regulator ArhGAP36 to the centrosome. Activating the Shh pathway results in the removal of ArhGAP36 from the mother centriole and the centrosomal PKA accumulation. This PKA then phosphorylates Inversin and promotes its interaction with and the ciliary translocation of Smoothened. Knockdown of Inversin disrupts the ciliary translocation of Smoothened and Shh pathway activation. These findings reveal a regulatory molecular mechanism for the initial step of Shh pathway activation.

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Yuan, Gongjie, Gurpreet Singh, Serafine Chen, Kristy Carrington Perez, Yan Wu, Bo Liu, and Jill Ann Helms. "Cleft Palate and Aglossia Result from Perturbations in Wnt and Hedgehog Signaling." Cleft Palate-Craniofacial Journal 54, no. 3 (May 2017): 269–80. http://dx.doi.org/10.1597/15-178.

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Objective The objective of this study was to explore the molecular basis for cleft secondary palate and arrested tongue development caused by the loss of the intraflagellar transport protein, Kif3a. Design Kif3a mutant embryos and their littermate controls were analyzed for defects in facial development at multiple stages of embryonic development. Histology was employed to understand the effects of Kif3a deletion on palate and tongue development. Various transgenic reporter strains were used to understand how deletion of Kif3a affected Hedgehog and Wnt signaling. Immunostaining for structural elements of the tongue and for components of the Wnt pathway were performed. BrdU activity analyses were carried out to examine how the loss of Kif3a affected cell proliferation and led to palate and tongue malformations. Results Kif3a deletion causes cranial neural crest cells to become unresponsive to Hedgehog signals and hyper-responsive to Wnt signals. This aberrant molecular signaling causes abnormally high cell proliferation, but paradoxically outgrowths of the tongue and the palatal processes are reduced. The basis for this enigmatic effect can be traced back to a disruption in epithelial/mesenchymal signaling that governs facial development. Conclusion The primary cilium is a cell surface organelle that integrates Hh and Wnt signaling, and disruptions in the function of the primary cilium cause one of the most common—of the rarest—craniofacial birth defects observed in humans. The shared molecular basis for these dysmorphologies is an abnormally high Wnt signal simultaneous with an abnormally low Hedgehog signal. These pathways are integrated in the primary cilium.

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Hoogendoorn, Sascha. "Small Molecules Targeting the Hedgehog Pathway: From Phenotype to Mechanistic Understanding." CHIMIA International Journal for Chemistry 74, no. 9 (September 30, 2020): 652–58. http://dx.doi.org/10.2533/chimia.2020.652.

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Since the beginning of 2019, the Hoogendoorn lab is active at the University of Geneva. We are a Chemical Biology lab and our research focuses on the Hedgehog (Hh) signalling pathway and the primary cilium, a small cellular organelle which corrects structure and function, is required to conduct the Hh signal. Ciliary Hh signalling plays an important role in embryonic development, and its dysregulation consequently results in developmental disorders as well as a variety of cancers. We use an interdisciplinary approach, ranging from organic chemistry to cell biology and genetics, to develop chemical tools to study and perturb ciliary signalling. In this account, I will highlight existing small molecules that target the Hh pathway, our efforts to discover new compounds, and the methodologies that we employ for target deconvolution and mechanism of action studies.

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Kiprilov, Enko N., Aashir Awan, Romain Desprat, Michelle Velho, Christian A. Clement, Anne Grete Byskov, Claus Y. Andersen, et al. "Human embryonic stem cells in culture possess primary cilia with hedgehog signaling machinery." Journal of Cell Biology 180, no. 5 (March 10, 2008): 897–904. http://dx.doi.org/10.1083/jcb.200706028.

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Human embryonic stem cells (hESCs) are potential therapeutic tools and models of human development. With a growing interest in primary cilia in signal transduction pathways that are crucial for embryological development and tissue differentiation and interest in mechanisms regulating human hESC differentiation, demonstrating the existence of primary cilia and the localization of signaling components in undifferentiated hESCs establishes a mechanistic basis for the regulation of hESC differentiation. Using electron microscopy (EM), immunofluorescence, and confocal microscopies, we show that primary cilia are present in three undifferentiated hESC lines. EM reveals the characteristic 9 + 0 axoneme. The number and length of cilia increase after serum starvation. Important components of the hedgehog (Hh) pathway, including smoothened, patched 1 (Ptc1), and Gli1 and 2, are present in the cilia. Stimulation of the pathway results in the concerted movement of Ptc1 out of, and smoothened into, the primary cilium as well as up-regulation of GLI1 and PTC1. These findings show that hESCs contain primary cilia associated with working Hh machinery.

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Ku, Pei-I., Jamuna S. Sreeja, Benjamin R. Myers, and Radhika Subramanian. "Real time imaging of the trafficking of a Hedgehog pathway kinesin in the primary cilium." Biophysical Journal 121, no. 3 (February 2022): 85a. http://dx.doi.org/10.1016/j.bpj.2021.11.2286.

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Girardet, Laura, Agathe Bernet, Ezéquiel Calvo, Denis Soulet, Charles Joly-Beauparlant, Arnaud Droit, Daniel G. Cyr, and Clémence Belleannée. "Hedgehog signaling pathway regulates gene expression profile of epididymal principal cells through the primary cilium." FASEB Journal 34, no. 6 (April 13, 2020): 7593–609. http://dx.doi.org/10.1096/fj.202000328r.

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Wang, Yu, Zhe Zhou, Christopher T. Walsh, and Andrew P. McMahon. "Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation." Proceedings of the National Academy of Sciences 106, no. 8 (February 5, 2009): 2623–28. http://dx.doi.org/10.1073/pnas.0812110106.

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Agbu, Stephanie O., Yinwen Liang, Aimin Liu, and Kathryn V. Anderson. "The small GTPase RSG1 controls a final step in primary cilia initiation." Journal of Cell Biology 217, no. 1 (October 16, 2017): 413–27. http://dx.doi.org/10.1083/jcb.201604048.

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Primary cilia, which are essential for normal development and tissue homeostasis, are extensions of the mother centriole, but the mechanisms that remodel the centriole to promote cilia initiation are poorly understood. Here we show that mouse embryos that lack the small guanosine triphosphatase RSG1 die at embryonic day 12.5, with developmental abnormalities characteristic of decreased cilia-dependent Hedgehog signaling. Rsg1 mutant embryos have fewer primary cilia than wild-type embryos, but the cilia that form are of normal length and traffic Hedgehog pathway proteins within the cilium correctly. Rsg1 mother centrioles recruit proteins required for cilia initiation and dock onto ciliary vesicles, but axonemal microtubules fail to elongate normally. RSG1 localizes to the mother centriole in a process that depends on tau tubulin kinase 2 (TTBK2), the CPLANE complex protein Inturned (INTU), and its own GTPase activity. The data suggest a specific role for RSG1 in the final maturation of the mother centriole and ciliary vesicle that allows extension of the ciliary axoneme.

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Drummond, Michael L., Mischa Li, Eric Tarapore, Tuyen T. L. Nguyen, Baina J. Barouni, Shaun Cruz, Kevin C. Tan, Anthony E. Oro, and Scott X. Atwood. "Actin polymerization controls cilia-mediated signaling." Journal of Cell Biology 217, no. 9 (June 26, 2018): 3255–66. http://dx.doi.org/10.1083/jcb.201703196.

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Primary cilia are polarized organelles that allow detection of extracellular signals such as Hedgehog (Hh). How the cytoskeleton supporting the cilium generates and maintains a structure that finely tunes cellular response remains unclear. Here, we find that regulation of actin polymerization controls primary cilia and Hh signaling. Disrupting actin polymerization, or knockdown of N-WASp/Arp3, increases ciliation frequency, axoneme length, and Hh signaling. Cdc42, a potent actin regulator, recruits both atypical protein pinase C iota/lambda (aPKC) and Missing-in-Metastasis (MIM) to the basal body to maintain actin polymerization and restrict axoneme length. Transcriptome analysis implicates the Src pathway as a major aPKC effector. aPKC promotes whereas MIM antagonizes Src activity to maintain proper levels of primary cilia, actin polymerization, and Hh signaling. Hh pathway activation requires Smoothened-, Gli-, and Gli1-specific activation by aPKC. Surprisingly, longer axonemes can amplify Hh signaling, except when aPKC is disrupted, reinforcing the importance of the Cdc42–aPKC–Gli axis in actin-dependent regulation of primary cilia signaling.

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Wen, Xiaohui, Cary K. Lai, Marie Evangelista, Jo-Anne Hongo, Frederic J. de Sauvage, and Suzie J. Scales. "Kinetics of Hedgehog-Dependent Full-Length Gli3 Accumulation in Primary Cilia and Subsequent Degradation." Molecular and Cellular Biology 30, no. 8 (February 12, 2010): 1910–22. http://dx.doi.org/10.1128/mcb.01089-09.

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ABSTRACT Hedgehog (Hh) signaling in vertebrates depends on intraflagellar transport (IFT) within primary cilia. The Hh receptor Patched is found in cilia in the absence of Hh and is replaced by the signal transducer Smoothened within an hour of Hh stimulation. By generating antibodies capable of detecting endogenous pathway transcription factors Gli2 and Gli3, we monitored their kinetics of accumulation in cilia upon Hh stimulation. Localization occurs within minutes of Hh addition, making it the fastest reported readout of pathway activity, which permits more precise temporal and spatial localization of Hh signaling events. We show that the species of Gli3 that accumulates at cilium tips is full-length and likely not protein kinase A phosphorylated. We also confirmed that phosphorylation and βTrCP/Cul1 are required for endogenous Gli3 processing and that this is inhibited by Hh. Surprisingly, however, Hh-dependent inhibition of processing does not lead to accumulation of full-length Gli3, but instead renders it labile, leading to its proteasomal degradation via the SPOP/Cul3 complex. In fact, full-length Gli3 disappears with faster kinetics than the Gli3 repressor, the latter not requiring SPOP/Cul3 or βTrCP/Cul1. This may contribute to the increased Gli3 activator/repressor ratios found in IFT mutants.

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Ritter, Andreas, Susanne Roth, Nina-Naomi Kreis, Alexandra Friemel, Samira Catharina Hoock, Alice Steglich Souto, Christine Eichbaum, et al. "Primary Cilia in Trophoblastic Cells." Hypertension 76, no. 5 (November 2020): 1491–505. http://dx.doi.org/10.1161/hypertensionaha.120.15433.

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The pathogenesis of preeclampsia, a pregnancy-related disease, is not completely understood. The primary cilium transduces a diverse array of signaling pathways important for vital cellular activities. Primary cilia were reported to facilitate trophoblastic cell invasion. We hypothesized their further functions in trophoblasts and were interested in related molecular mechanisms. We systematically examined the presence, length and percentage of the primary cilium, its mediated signal transduction, and its connection to trophoblast function. Various cellular and molecular methods were used including immunofluorescence staining, spheroid formation, gene analysis, invasion and tube formation assays with trophoblastic cell lines, primary trophoblasts, and placental tissues. We show that primary cilia are present in various trophoblastic cell lines derived from first trimester placentas. Cilia are also observable in primary trophoblasts, though in a small quantity. Importantly, primary cilia are shortened in trophoblastic cells derived from preeclamptic placentas. Mechanistically, interleukin-6, tumor necrosis factor-α or sera from patients with preeclampsia are able to reduce the length of primary cilia and impair the important sonic hedgehog signaling pathway. Functionally, trophoblastic cells with defective cilia display severe failures in their key functions, like migration, invasion and tube formation, also observed in trophoblastic cells depleted of the intraflagellar transport protein 88. This is accompanied by reduced gene expression of matrix metallopeptidases, vascular endothelial growth factor, and placental growth factor. This work highlights the significance of primary cilia in the functions of trophoblastic cells. Dysfunctional cilia may lead to compromised migration, invasion, and endothelial remodeling of trophoblastic cells, contributing to the development of preeclampsia.

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Milenkovic, Ljiljana, Matthew P. Scott, and Rajat Rohatgi. "Lateral transport of Smoothened from the plasma membrane to the membrane of the cilium." Journal of Cell Biology 187, no. 3 (October 26, 2009): 365–74. http://dx.doi.org/10.1083/jcb.200907126.

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The function of primary cilia depends critically on the localization of specific proteins in the ciliary membrane. A major challenge in the field is to understand protein trafficking to cilia. The Hedgehog (Hh) pathway protein Smoothened (Smo), a 7-pass transmembrane protein, moves to cilia when a ligand is received. Using microscopy-based pulse-chase analysis, we find that Smo moves through a lateral transport pathway from the plasma membrane to the ciliary membrane. Lateral movement, either via diffusion or active transport, is quite distinct from currently studied pathways of ciliary protein transport in mammals, which emphasize directed trafficking of Golgi-derived vesicles to the base of the cilium. We anticipate that this alternative route will be used by other signaling proteins that function at cilia. The path taken by Smo may allow novel strategies for modulation of Hh signaling in cancer and regeneration.

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Zhao, Haotian, and Tasneem Zahran. "MODL-30. DISSECTING THE ROLE OF MULTI-CILIOGENESIS NETWORK IN CHOROID PLEXUS TUMOR." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii417. http://dx.doi.org/10.1093/neuonc/noaa222.603.

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Abstract The choroid plexus (CP) in brain ventricles consists of a fibro-vascular core encapsulated by epithelial cells that possess clusters of primary cilia on cell surface. CP tumors are rare primary brain neoplasms that most commonly occur in young children. Compared to the benign CP papilloma, choroid plexus carcinoma (CPC) is poorly understood and highly lethal with few treatments available. Molecular, cytogenetics and genomics studies uncovered complex alterations in CPC including frequent chromosomal loss and recurrent focal aberrations, whereas abnormal NOTCH signaling is observed in many CP tumors. We showed that activation of both NOTCH and Sonic Hedgehog (SHH) signaling in mice drives the formation of aggressive CP tumor. Molecular and histology analyses demonstrated that these murine CP tumors closely resemble their human counterparts, which also display aberrant SHH and NOTCH signaling, suggesting they may represent potential therapeutic avenues. Indeed, treatment with vismodegib, an FDA-approved SHH pathway inhibitor, suppresses CP tumor growth. Unlike multi-ciliated CP epithelial cells, tumor cells in these animal models are characterized by a solitary primary cilium. Though key genes of the multi-ciliogenesis circuit driven by Geminin coiled-coil domain-containing protein 1 (GEMC1) are expressed in CP epithelium, GEMC1-dependent transcriptional program is suppressed in NOTCH-driven CP tumors. Importantly, CPCs in humans consist of tumor cells with a solitary primary cilium and exhibit profound defects multi-ciliogenesis program. Together, these results indicate that a solitary primary cilium is crucial for CPC development, whereas multi-ciliogenesis circuit possesses tumor suppressive functions and may represent a novel therapeutic target in CPC.

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Kunova Bosakova, Michaela, Alexandru Nita, Tomas Gregor, Miroslav Varecha, Iva Gudernova, Bohumil Fafilek, Tomas Barta, et al. "Fibroblast growth factor receptor influences primary cilium length through an interaction with intestinal cell kinase." Proceedings of the National Academy of Sciences 116, no. 10 (February 19, 2019): 4316–25. http://dx.doi.org/10.1073/pnas.1800338116.

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Vertebrate primary cilium is a Hedgehog signaling center but the extent of its involvement in other signaling systems is less well understood. This report delineates a mechanism by which fibroblast growth factor (FGF) controls primary cilia. Employing proteomic approaches to characterize proteins associated with the FGF-receptor, FGFR3, we identified the serine/threonine kinase intestinal cell kinase (ICK) as an FGFR interactor. ICK is involved in ciliogenesis and participates in control of ciliary length. FGF signaling partially abolished ICK’s kinase activity, through FGFR-mediated ICK phosphorylation at conserved residue Tyr15, which interfered with optimal ATP binding. Activation of the FGF signaling pathway affected both primary cilia length and function in a manner consistent with cilia effects caused by inhibition of ICK activity. Moreover, knockdown and knockout of ICK rescued the FGF-mediated effect on cilia. We provide conclusive evidence that FGF signaling controls cilia via interaction with ICK.

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Pal, Kasturi, Sun-hee Hwang, Bandarigoda Somatilaka, Hemant Badgandi, Peter K. Jackson, Kathryn DeFea, and Saikat Mukhopadhyay. "Smoothened determines β-arrestin–mediated removal of the G protein–coupled receptor Gpr161 from the primary cilium." Journal of Cell Biology 212, no. 7 (March 21, 2016): 861–75. http://dx.doi.org/10.1083/jcb.201506132.

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Dynamic changes in membrane protein composition of the primary cilium are central to development and homeostasis, but we know little about mechanisms regulating membrane protein flux. Stimulation of the sonic hedgehog (Shh) pathway in vertebrates results in accumulation and activation of the effector Smoothened within cilia and concomitant disappearance of a negative regulator, the orphan G protein–coupled receptor (GPCR), Gpr161. Here, we describe a two-step process determining removal of Gpr161 from cilia. The first step involves β-arrestin recruitment by the signaling competent receptor, which is facilitated by the GPCR kinase Grk2. An essential factor here is the ciliary trafficking and activation of Smoothened, which by increasing Gpr161–β-arrestin binding promotes Gpr161 removal, both during resting conditions and upon Shh pathway activation. The second step involves clathrin-mediated endocytosis, which functions outside of the ciliary compartment in coordinating Gpr161 removal. Mechanisms determining dynamic compartmentalization of Gpr161 in cilia define a new paradigm for down-regulation of GPCRs during developmental signaling from a specialized subcellular compartment.

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Gong, Siyi, Feng Ji, Bin Wang, Yingying Zhang, Xingshun Xu, and Miao Sun. "Tectonic Proteins Are Important Players in Non-Motile Ciliopathies." Cellular Physiology and Biochemistry 50, no. 1 (2018): 398–409. http://dx.doi.org/10.1159/000494017.

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Primary cilium is a ubiquitous, tiny organelle on the apex of the mammalian cells. Non-motile (primary) ciliopathies are diseases caused by the dysfunction of the primary cilium and they are characterized by diverse clinical and genetic heterogeneity. To date, nearly 200 genes have been shown to be associated with primary ciliopathies. Among them, tectonic genes are the important causative genes of ciliopathies. Tectonic proteins including TCTN1, TCTN2, and TCTN3 are important component proteins residing at the transition zone of cilia. Indeed, many ciliopathies have been reported to involve tectonics mutations, highlighting a pivotal role for tectonic proteins in ciliary functions. However, the specific functions of tectonic proteins remain largely enigmatic. Herein, we discuss the recent advances on the localization and structure of tectonic proteins and the functions of tectonic proteins. The increasing line of evidences demonstrates that tectonic proteins are required for ciliogenesis and regulate ciliary membrane composition. More importantly, Tectonic proteins play a vital role in the regulation of the Sonic Hedgehog (Shh) pathway; Tectonic deficient mice show the Shh pathway-related developmental defects. Tectonic proteins share similar functions including neural patterning and Gli3 processing but also each has a unique and indispensable role in the ciliogenesis and signaling pathways. At the same time, the mutations of tectonic genes are the causes of a serial of primary ciliopathies including Meckel-Gruber syndrome, Oral-facial-digital syndrome, and Joubert syndrome. Therefore, full understanding of functions of tectonic proteins will help to crack ciliopathies and improve life quality of patients by future gene therapy.

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Bangs, Fiona K., Paul Miller, and Eric O'Neill. "Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse." Disease Models & Mechanisms 13, no. 7 (June 22, 2020): dmm044289. http://dx.doi.org/10.1242/dmm.044289.

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ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths worldwide, but has a 5-year survival rate of only 7% primarily due to late diagnosis and ineffective therapies. To treat or even prevent PDAC, it is vital that we understand the initiating events that lead to tumour onset. PDAC develops from preneoplastic lesions, most commonly pancreatic intraepithelial neoplasias (PanINs), driven by constitutive activation of KRAS. In patients, PanINs are associated with regions of acinar-to-ductal metaplasia (ADM) where, in response to inflammation, acini dedifferentiate to a pancreatic progenitor-like fate. In healthy tissue this process is reversible leading to regeneration of the pancreas; however, in the presence of oncogenic KRAS, regeneration is blocked and ADM can give rise to PanIN lesions. Here, we used a 3D mouse acinar culture that recapitulates ADM in vitro to explore how KRAS prevents regeneration. Regeneration is regulated by Hedgehog (Hh) signalling, which is transduced via the primary cilium. In wild-type acini, cilia assemble upon ADM and Hh target gene expression is upregulated; however, ciliogenesis and Hh signalling are suppressed during ADM in cells expressing oncogenic KRAS. We show that ciliogenesis fails due to ectopic activation of the cilium disassembly pathway, which is mediated by AurkA, a direct transcriptional target of KRAS. Inhibition of AurkA is able to rescue primary cilia and restore Hh signalling. We suggest that this could be used as a mechanism to prevent the formation of early lesions and thereby prevent progression to PDAC.

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Flanagan, Anne-Marie, Elena Stavenschi, Shivakumar Basavaraju, David Gaboriau, David A. Hoey, and Ciaran G. Morrison. "Centriole splitting caused by loss of the centrosomal linker protein C-NAP1 reduces centriolar satellite density and impedes centrosome amplification." Molecular Biology of the Cell 28, no. 6 (March 15, 2017): 736–45. http://dx.doi.org/10.1091/mbc.e16-05-0325.

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Duplication of the centrosomes is a tightly regulated process. Abnormal centrosome numbers can impair cell division and cause changes in how cells migrate. Duplicated centrosomes are held together by a proteinaceous linker made up of rootletin filaments anchored to the centrioles by C-NAP1. This linker is removed in a NEK2A kinase-dependent manner as mitosis begins. To explore C-NAP1 activities in regulating centrosome activities, we used genome editing to ablate it. C-NAP1–null cells were viable and had an increased frequency of premature centriole separation, accompanied by reduced density of the centriolar satellites, with reexpression of C-NAP1 rescuing both phenotypes. We found that the primary cilium, a signaling structure that arises from the mother centriole docked to the cell membrane, was intact in the absence of C-NAP1, although components of the ciliary rootlet were aberrantly localized away from the base of the cilium. C-NAP1–deficient cells were capable of signaling through the cilium, as determined by gene expression analysis after fluid flow–induced shear stress and the relocalization of components of the Hedgehog pathway. Centrosome amplification induced by DNA damage or by PLK4 or CDK2 overexpression was markedly reduced in the absence of C-NAP1. We conclude that centriole splitting reduces the local density of key centriolar precursors to impede overduplication.

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Martin-Hurtado, Ana, Isabel Lastres-Becker, Antonio Cuadrado, and Francesc R. Garcia-Gonzalo. "NRF2 and Primary Cilia: An Emerging Partnership." Antioxidants 9, no. 6 (June 2, 2020): 475. http://dx.doi.org/10.3390/antiox9060475.

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When not dividing, many cell types target their centrosome to the plasma membrane, where it nucleates assembly of a primary cilium, an antenna-like signaling structure consisting of nine concentric microtubule pairs surrounded by membrane. Primary cilia play important pathophysiological roles in many tissues, their dysfunction being associated with cancer and ciliopathies, a diverse group of congenital human diseases. Several recent studies have unveiled functional connections between primary cilia and NRF2 (nuclear factor erythroid 2-related factor 2), the master transcription factor orchestrating cytoprotective responses to oxidative and other cellular stresses. These NRF2-cilia relationships are reciprocal: primary cilia, by promoting autophagy, downregulate NRF2 activity. In turn, NRF2 transcriptionally regulates genes involved in ciliogenesis and Hedgehog (Hh) signaling, a cilia-dependent pathway with major roles in embryogenesis, stem cell function and tumorigenesis. Nevertheless, while we found that NRF2 stimulates ciliogenesis and Hh signaling, a more recent study reported that NRF2 negatively affects these processes. Herein, we review the available evidence linking NRF2 to primary cilia, suggest possible explanations to reconcile seemingly contradictory data, and discuss what the emerging interplay between primary cilia and NRF2 may mean for human health and disease.

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Franchi, Federico, Karen M. Peterson, Katherine Quandt, David Domnick, Timothy L. Kline, Michaela Olthoff, Mojtaba Parvizi, et al. "Impaired Hedgehog-Gli1 Pathway Activity Underlies the Vascular Phenotype of Polycystic Kidney Disease." Hypertension 76, no. 6 (December 2020): 1889–97. http://dx.doi.org/10.1161/hypertensionaha.120.15483.

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Polycystic kidney disease (PKD) has been linked to abnormal structure/function of ciliary proteins, leading to renal dysfunction. Recently, attention has been focused in the significant vascular abnormalities associated with PKD, but the mechanisms underlying this phenomenon remain elusive. Here, we seek to define the molecular events regulating the angiogenic imbalance observed in PKD. Using micro computed tomography (n=7) and protein expression analysis (n=5), we assessed the vascular density and the angiogenic profile of noncystic organs in a well-established PKD rat model (Polycystic Kidney-PCK rat). Heart and lungs of PCK rats have reduced vascular density and decreased expression of angiogenic factors compared with wild type. Similarly, PCK-vascular smooth muscle cells (VSMCs; n=4) exhibited lower levels of vascular markers. Then, using small interfering RNA (n=4), we determined the role of the ciliary protein fibrocystin in wild type-VSMCs, a critical component/regulator of vascular structure and function. Reduction of fibrocystin in wild type-VSMCs (n=4) led to an abnormal angiogenic potential similar to that observed in PCK-VSMCs. Furthermore, we investigated the involvement of the hedgehog signaling, a pathway closely linked to the primary cilium and associated with vascular development, in PKD. Mechanistically, we demonstrated that impairment of the hedgehog signaling mediates, in part, this abnormal angiogenic phenotype. Lastly, overexpression of Gli1 in PCK-VSMCs (n=4) restored the expression levels of proangiogenic molecules. Our data support a critical role of fibrocystin in the abnormal vascular phenotype of PKD and indicate that a dysregulation of hedgehog may be responsible, at least in part, for these vascular deficiencies.

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Bay, Sarah N., Alyssa B. Long, and Tamara Caspary. "Disruption of the ciliary GTPase Arl13b suppresses Sonic hedgehog overactivation and inhibits medulloblastoma formation." Proceedings of the National Academy of Sciences 115, no. 7 (January 29, 2018): 1570–75. http://dx.doi.org/10.1073/pnas.1706977115.

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Medulloblastoma (MB) is the most common malignant pediatric brain tumor, and overactivation of the Sonic Hedgehog (Shh) signaling pathway, which requires the primary cilium, causes 30% of MBs. Current treatments have known negative side effects or resistance mechanisms, so new treatments are necessary. Shh signaling mutations, like those that remove Patched1 (Ptch1) or activate Smoothened (Smo), cause tumors dependent on the presence of cilia. Genetic ablation of cilia prevents these tumors by removing Gli activator, but cilia are a poor therapeutic target since they support many biological processes. A more appropriate strategy would be to identify a protein that functionally disentangles Gli activation and ciliogenesis. Our mechanistic understanding of the ciliary GTPase Arl13b predicts that it could be such a target. Arl13b mutants retain short cilia, and loss of Arl13b results in ligand-independent, constitutive, low-level pathway activation but prevents maximal signaling without disrupting Gli repressor. Here, we show that deletion of Arl13b reduced Shh signaling levels in the presence of oncogenic SmoA1, suggesting Arl13b acts downstream of known tumor resistance mechanisms. Knockdown of ARL13B in human MB cell lines and in primary mouse MB cell culture decreased proliferation. Importantly, loss of Arl13b in a Ptch1-deleted mouse model of MB inhibited tumor formation. Postnatal depletion of Arl13b does not lead to any overt phenotypes in the epidermis, liver, or cerebellum. Thus, our in vivo and in vitro studies demonstrate that disruption of Arl13b inhibits cilia-dependent oncogenic Shh overactivation.

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Nachury, Maxence V. "How do cilia organize signalling cascades?" Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1650 (September 5, 2014): 20130465. http://dx.doi.org/10.1098/rstb.2013.0465.

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Cilia and flagella are closely related centriole-nucleated protrusions of the cell with roles in motility and signal transduction. Two of the best-studied signalling pathways organized by cilia are the transduction cascade for the morphogen Hedgehog in vertebrates and the mating pathway that initiates gamete fusion in the unicellular green alga Chlamydomonas reinhardtii . What is the role of cilia in these signalling transduction cascades? In both Hedgehog and mating pathways, all signalling intermediates have been found to localize to cilia, and, for some signalling factors, ciliary localization is regulated by pathway activation. Given a concentration factor of three orders of magnitude provided by translocating a protein into the cilium, the compartment model proposes that cilia act as miniaturized reaction tubes bringing signalling factors and processing enzymes in close proximity. On the other hand, the scaffolding model views the intraflagellar transport machinery, whose primary function is to build cilia and flagella, as a molecular scaffold for the mating transduction cascade at the flagellar membrane. While these models may coexist, it is hoped that a precise understanding of the mechanisms that govern signalling inside cilia will provide a satisfying answer to the question ‘how do cilia organize signalling?’. This review covers the evidence supporting each model of signalling and outlines future directions that may address which model applies in given biological settings.

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Chippalkatti, Rohan, and Daniel Abankwa. "Promotion of cancer cell stemness by Ras." Biochemical Society Transactions 49, no. 1 (February 5, 2021): 467–76. http://dx.doi.org/10.1042/bst20200964.

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Cancer stem cells (CSC) may be the most relevant and elusive cancer cell population, as they have the exquisite ability to seed new tumors. It is plausible, that highly mutated cancer genes, such as KRAS, are functionally associated with processes contributing to the emergence of stemness traits. In this review, we will summarize the evidence for a stemness driving activity of oncogenic Ras. This activity appears to differ by Ras isoform, with the highly mutated KRAS having a particularly profound impact. Next to established stemness pathways such as Wnt and Hedgehog (Hh), the precise, cell cycle dependent orchestration of the MAPK-pathway appears to relay Ras activation in this context. We will examine how non-canonical activities of K-Ras4B (hereafter K-Ras) could be enabled by its trafficking chaperones calmodulin and PDE6D/PDEδ. Both dynamically localize to the cellular machinery that is intimately linked to cell fate decisions, such as the primary cilium and the centrosome. Thus, it can be speculated that oncogenic K-Ras disrupts fundamental polarized signaling and asymmetric apportioning processes that are necessary during cell differentiation.

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Lauter, Gilbert, Andrea Coschiera, Masahito Yoshihara, Debora Sugiaman-Trapman, Sini Ezer, Shalini Sethurathinam, Shintaro Katayama, Juha Kere, and Peter Swoboda. "Differentiation of ciliated human midbrain-derived LUHMES neurons." Journal of Cell Science 133, no. 21 (October 28, 2020): jcs249789. http://dx.doi.org/10.1242/jcs.249789.

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ABSTRACTMany human cell types are ciliated, including neural progenitors and differentiated neurons. Ciliopathies are characterized by defective cilia and comprise various disease states, including brain phenotypes, where the underlying biological pathways are largely unknown. Our understanding of neuronal cilia is rudimentary, and an easy-to-maintain, ciliated human neuronal cell model is absent. The Lund human mesencephalic (LUHMES) cell line is a ciliated neuronal cell line derived from human fetal mesencephalon. LUHMES cells can easily be maintained and differentiated into mature, functional neurons within one week. They have a single primary cilium as proliferating progenitor cells and as postmitotic, differentiating neurons. These developmental stages are completely separable within one day of culture condition change. The sonic hedgehog (SHH) signaling pathway is active in differentiating LUHMES neurons. RNA-sequencing timecourse analyses reveal molecular pathways and gene-regulatory networks critical for ciliogenesis and axon outgrowth at the interface between progenitor cell proliferation, polarization and neuronal differentiation. Gene expression dynamics of cultured LUHMES neurons faithfully mimic the corresponding in vivo dynamics of human fetal midbrain. In LUHMES cells, neuronal cilia biology can be investigated from proliferation through differentiation to mature neurons.

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Dustin, Michael L. "T-cells play the classics with a different spin." Molecular Biology of the Cell 25, no. 11 (June 2014): 1699–703. http://dx.doi.org/10.1091/mbc.e13-11-0636.

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The immune system uses much of the classic machinery of cell biology, but in ways that put a different spin on organization and function. Striking recent examples include the demonstration of intraflagellar transport protein and hedgehog contributions to the immune synapse, even though immune cells lack a primary cilium that would be the typical setting for this machinery. In a second example, lymphocytes have their own subfamily of integrins, the β2 subfamily, and only integrins in this family form a stable adhesion ring using freely mobile ligands, a key feature of the immunological synapse. Finally, we showed recently that T-cells use endosomal sorting complexes required for transport (ESCRTs) at the plasma membrane to generate T-cell antigen receptor–enriched microvesicles. It is unusual for the ESCRT pathway to operate at the plasma membrane, but this may allow a novel form of cell–cell communication by providing a multivalent ligand for major histocompatibility complex–peptide complexes and perhaps other receptors on the partnering B-cell. Immune cells are thus an exciting system for novel cell biology even with classical pathways that have been studied extensively in other cell types.

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Wang, Yuliang, Abdiasis M. Hussein, Logeshwaran Somasundaram, Rithika Sankar, Damien Detraux, Julie Mathieu, and Hannele Ruohola-Baker. "microRNAs Regulating Human and Mouse Naïve Pluripotency." International Journal of Molecular Sciences 20, no. 23 (November 22, 2019): 5864. http://dx.doi.org/10.3390/ijms20235864.

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microRNAs are ~22bp nucleotide non-coding RNAs that play important roles in the post-transcriptional regulation of gene expression. Many studies have established that microRNAs are important for cell fate choices, including the naïve to primed pluripotency state transitions, and their intermediate state, the developmentally suspended diapause state in early development. However, the full extent of microRNAs associated with these stage transitions in human and mouse remain under-explored. By meta-analysis of microRNA-seq, RNA-seq, and metabolomics datasets from human and mouse, we found a set of microRNAs, and importantly, their experimentally validated target genes that show consistent changes in naïve to primed transitions (microRNA up, target genes down, or vice versa). The targets of these microRNAs regulate developmental pathways (e.g., the Hedgehog-pathway), primary cilium, and remodeling of metabolic processes (oxidative phosphorylation, fatty acid metabolism, and amino acid transport) during the transition. Importantly, we identified 115 microRNAs that significantly change in the same direction in naïve to primed transitions in both human and mouse, many of which are novel candidate regulators of pluripotency. Furthermore, we identified 38 microRNAs and 274 target genes that may be involved in diapause, where embryonic development is temporarily suspended prior to implantation to uterus. The upregulated target genes suggest that microRNAs activate stress response in the diapause stage. In conclusion, we provide a comprehensive resource of microRNAs and their target genes involved in naïve to primed transition and in the paused intermediate, the embryonic diapause stage.

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Yıldız Bölükbaşı, Esra, Sara Mumtaz, Muhammad Afzal, Ute Woehlbier, Sajid Malik, and Aslıhan Tolun. "Homozygous mutation in CEP19, a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly." Journal of Medical Genetics 55, no. 3 (November 10, 2017): 189–97. http://dx.doi.org/10.1136/jmedgenet-2017-104758.

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BackgroundBardet-Biedl syndrome (BBS) is a ciliopathy with extensive phenotypic variability and genetic heterogeneity. We aimed to discover the gene mutated in a consanguineous kindred with multiple cases of a BBS phenotype.MethodsSNP genotype data were used for linkage analysis and exome sequencing to identify mutations. Modelling and in silico analysis were performed to predict mutation severity.ResultsPatients had postaxial polydactyly plus variable other clinical features including rod-cone dystrophy, obesity, intellectual disability, renal malformation, developmental delay, dental anomalies, speech disorder and enlarged fatty liver. The 4.57 Mb disease locus harboured homozygous, truncating CEP19 c.194_195insA (p.Tyr65*) mutation. We also found glioma-associated oncogene homolog 1(GLI1) c.820G>C (p.Gly274Arg) in the homozygous state in most patients. In silico modelling strongly suggests that it is damaging. Also, different combinations of four possible modifier alleles in BBS-related genes were detected. Two are known modifier alleles for BBS, splicing variant CCDC28B c.330C>T and missense MKKS/BBS6 p.Ile339Val, and the others are C8ORF37/BBS21 p.Ala178Val and TMEM67/BBS14 modifier p.Asp799Asp. Some patients carry all those five known/possible modifier alleles. Such variants are highly significantly more abundant in our patients than in a control group.ConclusionCEP19 encodes a centrosomal and ciliary protein, as all BBS genes do. Another truncating mutation p.Arg82* has been reported as responsible for morbid obesity in a family; however, in the family we present, not all homozygotes are obese, although some are severely obese. The variant in GLI1, encoding a transcription factor that localises to the primary cilium and nucleus and is a mediator of the sonic hedgehog pathway, possibly exacerbates disease severity when in the homozygous state.

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Offin, Michael, Jennifer L. Sauter, Jacklyn V. Egger, Elisa deStanchina, John T. Poirier, Marjorie G. Zauderer, Charles Rudin, and Triparna Sen. "Abstract 51: Multiomic profiling of patient-derived xenografts established from patients with malignant pleural mesothelioma proposes pathways associated with poor prognosis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 51. http://dx.doi.org/10.1158/1538-7445.am2022-51.

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Abstract Background: Despite recent treatment advances, malignant pleural mesothelioma (MPM) is an aggressive, recalcitrant malignancy. Currently, histologic subtype (epithelioid/non-epithelioid/biphasic) is the primary prognostic factor; other potential biomarkers to guide therapeutic strategies remain elusive. Even with multimodality therapies, recurrence is high in early-stage disease. In the unresectable/metastatic setting, there are only two FDA approved regimens, both in the first line setting: cisplatin/pemetrexed and ipilimumab/nivolumab. Unfortunately, most who respond to first line treatment experience disease progression within a year. A few established MPM cell lines, with inherent limitations, provide minimal preclinical insight. The relative lack of model systems that accurately reflect MPM tumorigenesis is a barrier to therapeutic and diagnostic advances in MPM. Methods: We developed a diverse library of 22 extensively annotated patient-derived xenograft (PDX) models from 22 patients with MPM. Multi-omic analyses including, targeted tumor next-generation sequencing by MSK-IMPACT, RNA-sequencing, and immunohistochemistry was performed. We deconvoluted the mutational landscapes, global expression profiles, and molecular subtypes of these MPM models and further compared the PDXs to MPM clinical specimens, including matched PDX and primary tumor pairs. Results: The mutational landscapes of PDX models strongly correlated with paired tumor samples. There were some differences in CDKN2A/B mutations and relative enrichment of NF2 with fewer BAP1 alterations, the significance of which is being investigated. When compared by histological subtype, we observed an upregulation of genes involved in NOTCH and EMT signaling in the epithelioid models. Models derived from patients with shorter overall survival or poor response to platinum doublet had higher expression of WNT/β-catenin signaling, hedgehog pathway, and epithelial-mesenchymal transition signaling as well as downregulation of immune-activation pathways, including type I and II interferon signaling and inflammatory response pathways. Conclusions: This library of MPM PDXs, the largest to date, effectively mimics human disease and provides unprecedented insight into the genomic, transcriptomic, and protein landscape of MPM. These PDX models will inform future clinical investigations and provide an important new preclinical resource. Citation Format: Michael Offin, Jennifer L. Sauter, Jacklyn V. Egger, Elisa deStanchina, John T. Poirier, Marjorie G. Zauderer, Charles Rudin, Triparna Sen. Multiomic profiling of patient-derived xenografts established from patients with malignant pleural mesothelioma proposes pathways associated with poor prognosis [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 51.

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Iannello, Grazia, Cecilia Sena, Lynn Pais, Ellie Seaby, Radha Sathanayagam, Nia Ebrahim, Casie Genetti, et al. "Genetic Study in a Cohort of Children With ROHHAD Syndrome." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A503—A504. http://dx.doi.org/10.1210/jendso/bvab048.1028.

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Abstract Introduction: Rapid-onset obesity, hypoventilation, hypothalamic dysfunction and autonomic dysregulation (ROHHAD) is a rare syndrome beginning at 3-6 years of age with approximately 150 cases described. Additional features include eye abnormalities, neurobehavioral dysfunction and paraneoplastic tumors. The etiology of the complex phenotype remains unknown. Methods: This study aims to investigate the genetic landscape of this complex phenotype by whole exome sequencing (WES) and copy number variation (CNV) analysis. We recruited 33 families (27 trios, 1 duo and 5 singletons) with a proband with ROHHAD syndrome (Ize-Ludlow 2007, Pediatrics). WES of 89 individuals was performed at the Center for Mendelian Genomics, Broad Institute. The Illumina platform with a mean coverage of ~100X (> 90% targets 20x) and Infinium Global Screening Array BeadChip 24v1.0 were used. Results: This report includes 28 probands (female = 18, 64%) with rapid onset obesity (100%), hypoventilation (88%), hypothalamic dysfunction (69%), eye disorders (62%) and neurobehavioral abnormalities (76%). Neuroendocrine tumor, ganglioneuroblastoma, was present in 38% (n=13). No unifying causative single gene or CNV was identified, but a number of sequence variants are prioritized. ARNT2, which encodes for a helix-loop-helix transcription factor, plays a role in the development of the hypothalamic-pituitary axis, postnatal brain growth, and visual and renal function. The de novo monoallelic missense variant was found in a 14-year old white girl (BMIz +3.25) with extreme obesity and a neurobehavioral phenotype. OCRL1, a multi-domain protein involved in cytoskeleton-plasma membrane adhesion, endosomal trafficking and in primary cilium assembly. Mutations in this gene have also been known to cause Lowe syndrome. A hemizygous X-linked frameshift variant in a 5-year old white boy with extreme obesity (BMIz +5.48), central hypoventilation neurobehavioral dysfunction and ganglioneuroblastoma. A monoallelic missense variant in NSD1, a transcriptional intermediary factor acting as a histone methyltransferase, was identified in a 8-year old Hispanic girl with severe obesity (BMIz +2.91), neurobehavioral disorder, pituitary and eye dysfunction and ganglioneuroblastoma. NSD1 is known to cause Sotos and Beckwith-Wiedemann. Compound heterozygous variants in KIF7, a key component of the Hedgehog signaling pathway, were identified in a 14-year old white girl with severe obesity (BMIz +3.00), autistic behavior, pituitary dysfunction and central hypoventilation. This gene is known to cause autosomal recessive hydrolethalis and acroscallosal syndromes with mutations also noted in Bardet-Biedl, Meckel and Joubert syndromes. Conclusion: While no unifying genetic cause has been identified in ROHHAD syndrome, it is possible that the phenotype represents a collection of complex genetic syndromes.

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Geoghegan, Ivor P., Laoise M. McNamara, and David A. Hoey. "Estrogen withdrawal alters cytoskeletal and primary ciliary dynamics resulting in increased Hedgehog and osteoclastogenic paracrine signalling in osteocytes." Scientific Reports 11, no. 1 (April 29, 2021). http://dx.doi.org/10.1038/s41598-021-88633-6.

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AbstractEstrogen deficiency during post-menopausal osteoporosis leads to osteoclastogenesis and bone loss. Increased pro-osteoclastogenic signalling (RANKL/OPG) by osteocytes occurs following estrogen withdrawal (EW) and is associated with impaired focal adhesions (FAs) and a disrupted actin cytoskeleton. RANKL production is mediated by Hedgehog signalling in osteocytes, a signalling pathway associated with the primary cilium, and the ciliary structure is tightly coupled to the cytoskeleton. Therefore, the objective of this study was to investigate the role of the cilium and associated signalling in EW-mediated osteoclastogenic signalling in osteocytes. We report that EW leads to an elongation of the cilium and increase in Hedgehog and osteoclastogenic signalling. Significant trends were identified linking cilia elongation with reductions in cell area and % FA area/cell area, indicating that cilia elongation is associated with disruption of FAs and actin contractility. To verify this, we inhibited FA assembly via αvβ3 antagonism and inhibited actin contractility and demonstrated an elongated cilia and increased expression of Hh markers and Rankl expression. Therefore, our results suggest that the EW conditions associated with osteoporosis lead to a disorganisation of αvβ3 integrins and reduced actin contractility, which were associated with an elongation of the cilium, activation of the Hh pathway and osteoclastogenic paracrine signalling.

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Findakly, Sarah, Vikas Daggubati, Galo Garcia, Sydney A. LaStella, Abrar Choudhury, Cecilia Tran, Amy Li, et al. "Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway." Journal of Cell Biology 220, no. 1 (December 7, 2020). http://dx.doi.org/10.1083/jcb.202002026.

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Vertebrate Hedgehog signals are transduced through the primary cilium, a specialized lipid microdomain that is required for Smoothened activation. Cilia-associated sterol and oxysterol lipids bind to Smoothened to activate the Hedgehog pathway, but how ciliary lipids are regulated is incompletely understood. Here we identified DHCR7, an enzyme that produces cholesterol, activates the Hedgehog pathway, and localizes near the ciliary base. We found that Hedgehog stimulation negatively regulates DHCR7 activity and removes DHCR7 from the ciliary microenvironment, suggesting that DHCR7 primes cilia for Hedgehog pathway activation. In contrast, we found that Hedgehog stimulation positively regulates the oxysterol synthase CYP7A1, which accumulates near the ciliary base and produces oxysterols that promote Hedgehog signaling in response to pathway activation. Our results reveal that enzymes involved in lipid biosynthesis in the ciliary microenvironment promote Hedgehog signaling, shedding light on how ciliary lipids are established and regulated to transduce Hedgehog signals.

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Pejskova, Petra, Madeline Louise Reilly, Lucia Bino, Ondrej Bernatik, Linda Dolanska, Ranjani Sri Ganji, Zbynek Zdrahal, Alexandre Benmerah, and Lukas Cajanek. "KIF14 controls ciliogenesis via regulation of Aurora A and is important for Hedgehog signaling." Journal of Cell Biology 219, no. 6 (April 29, 2020). http://dx.doi.org/10.1083/jcb.201904107.

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Primary cilia play critical roles in development and disease. Their assembly and disassembly are tightly coupled to cell cycle progression. Here, we present data identifying KIF14 as a regulator of cilia formation and Hedgehog (HH) signaling. We show that RNAi depletion of KIF14 specifically leads to defects in ciliogenesis and basal body (BB) biogenesis, as its absence hampers the efficiency of primary cilium formation and the dynamics of primary cilium elongation, and disrupts the localization of the distal appendage proteins SCLT1 and FBF1 and components of the IFT-B complex. We identify deregulated Aurora A activity as a mechanism contributing to the primary cilium and BB formation defects seen after KIF14 depletion. In addition, we show that primary cilia in KIF14-depleted cells are defective in response to HH pathway activation, independently of the effects of Aurora A. In sum, our data point to KIF14 as a critical node connecting cell cycle machinery, effective ciliogenesis, and HH signaling.

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Cai, Eva, Jingyi Zhang, and Xuecai Ge. "Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium." Science China Life Sciences, September 7, 2021. http://dx.doi.org/10.1007/s11427-021-1975-9.

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Gigante, Eduardo D., and Tamara Caspary. "Signaling in the primary cilium through the lens of the Hedgehog pathway." WIREs Developmental Biology 9, no. 6 (February 21, 2020). http://dx.doi.org/10.1002/wdev.377.

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Alves, Maíra Bianchi Rodrigues, Laura Girardet, Céline Augière, Kyeong Hye Moon, Camille Lavoie-Ouellet, Agathe Bernet, Denis Soulet, et al. "Hedgehog signaling regulates Wolffian duct development through the primary cilium." Biology of Reproduction, December 15, 2022. http://dx.doi.org/10.1093/biolre/ioac210.

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Abstract Primary cilia play pivotal roles in embryonic patterning and organogenesis through transduction of the Hedgehog signaling pathway (Hh). While mutations in Hh morphogens impair the development of the gonads and trigger male infertility, the contribution of Hh and primary cilia in the development of male reproductive ductules, including the epididymis, remains unknown. From a Pax2Cre; Ift88fl/fl knock-out mouse model, we found that primary cilia deletion is associated with imbalanced Hh signaling and morphometric changes in the Wolffian duct (WD), the embryonic precursor of the epididymis. Similar effects were observed following pharmacological blockade of primary cilia formation and Hh modulation on WD organotypic cultures. The expression of genes involved in extracellular matrix (ECM), mesenchymal-epithelial transition, canonical Hh, and WD development was significantly altered after treatments. Altogether, we identified the primary cilia-dependent Hh signaling as a master regulator of genes involved in WD development. This provides new insights regarding the etiology of sexual differentiation and male infertility issues.

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Jiang, Jason Y., Jeffrey L. Falcone, Silvana Curci, and Aldebaran M. Hofer. "Direct visualization of cAMP signaling in primary cilia reveals up-regulation of ciliary GPCR activity following Hedgehog activation." Proceedings of the National Academy of Sciences, May 29, 2019, 201819730. http://dx.doi.org/10.1073/pnas.1819730116.

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The primary cilium permits compartmentalization of specific signaling pathways, including elements of the Hedgehog (Hh) pathway. Hh transcriptional activity is thought to be negatively regulated by constitutively high ciliary cAMP maintained by the Gα(s)-coupled GPCR, GPR161. However, cilia also sequester many other Gα(s)-coupled GPCRs with unknown potential to regulate Hh. Here we used biosensors optimized for ciliary cAMP and strategies to isolate signals in the cilium from the cell body and neighboring cells. We found that ciliary cAMP was not elevated relative to cellular cAMP, inconsistent with constitutive cAMP production. Gα(s)-coupled GPCRs (e.g., the 5-HT6 serotonin and D1R dopamine receptor) had reduced ability to generate cAMP upon trafficking to the ciliary membrane. However, activation of the Hh pathway restored or amplified GPCR function to permit cAMP elevation selectively in the cilium. Hh therefore enables its own local GPCR-dependent cAMP regulatory circuit. Considering that GPCRs comprise much of the druggable genome, these data suggest alternative strategies to modify Hh signaling.

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Odabasi, Ezgi, Deniz Conkar, Jovana Deretic, Umut Batman, Kari-Anne M. Frikstad, Sebastian Patzke, and Elif Nur Firat-Karalar. "CCDC66 regulates primary cilium length and signaling via interactions with transition zone and axonemal proteins." Journal of Cell Science, January 6, 2023. http://dx.doi.org/10.1242/jcs.260327.

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The primary cilium is a microtubule-based organelle that serves as a hub for many signaling pathways. It functions as part of the centrosome/cilium complex, which also contains the basal body and the centriolar satellites. Little is known about the mechanisms by which the microtubule-based ciliary axoneme is assembled with proper length and structure, particularly in terms of the activity of microtubule-associated proteins (MAPs) and the crosstalk between the different compartments of the centrosome/cilium complex. Here, we analyzed CCDC66, a MAP implicated in cilium biogenesis and ciliopathies. Live-cell imaging revealed that CCDC66 compartmentalizes between centrosomes, centriolar satellites, and ciliary axoneme and tip during cilium biogenesis. CCDC66 depletion in human cells causes defects in cilium assembly, length and morphology. Notably, CCDC66 interacts with the ciliopathy-linked MAPs CEP104 and CSPP1 and regulates axonemal length and Hedgehog pathway activation. Moreover, CCDC66 is required for the basal body recruitment of transition zone proteins and IFT-B machinery. Overall, our results establish CCDC66 as a multifaceted regulator of the primary cilium and propose insight into how ciliary MAPs and subcompartments cooperate to ensure assembly of functional cilia.

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Alsolami, Mona, Stefanie Kuhns, Manal Alsulami, and Oliver E. Blacque. "ERICH3 in Primary Cilia Regulates Cilium Formation and the Localisations of Ciliary Transport and Sonic Hedgehog Signaling Proteins." Scientific Reports 9, no. 1 (November 11, 2019). http://dx.doi.org/10.1038/s41598-019-52830-1.

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Abstract Intraflagellar transport (IFT) is essential for the formation and function of the microtubule-based primary cilium, which acts as a sensory and signalling device at the cell surface. Consisting of IFT-A/B and BBSome cargo adaptors that associate with molecular motors, IFT transports protein into (anterograde IFT) and out of (retrograde IFT) the cilium. In this study, we identify the mostly uncharacterised ERICH3 protein as a component of the mammalian primary cilium. Loss of ERICH3 causes abnormally short cilia and results in the accumulation of IFT-A/B proteins at the ciliary tip, together with reduced ciliary levels of retrograde transport regulators, ARL13B, INPP5E and BBS5. We also show that ERICH3 ciliary localisations require ARL13B and BBSome components. Finally, ERICH3 loss causes positive (Smoothened) and negative (GPR161) regulators of sonic hedgehog signaling (Shh) to accumulate at abnormally high levels in the cilia of pathway-stimulated cells. Together, these findings identify ERICH3 as a novel component of the primary cilium that regulates cilium length and the ciliary levels of Shh signaling molecules. We propose that ERICH3 functions within retrograde IFT-associated pathways to remove signaling proteins from cilia.

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Hantel, Friederike, Huaize Liu, Lisa Fechtner, Herbert Neuhaus, Jie Ding, Danilo Arlt, Peter Walentek, et al. "Cilia-localized GID/CTLH ubiquitin ligase complex regulates protein homeostasis of sonic hedgehog signaling components." Journal of Cell Science 135, no. 9 (May 1, 2022). http://dx.doi.org/10.1242/jcs.259209.

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ABSTRACT Cilia are evolutionarily conserved organelles that orchestrate a variety of signal transduction pathways, such as sonic hedgehog (SHH) signaling, during embryonic development. Our recent studies have shown that loss of GID ubiquitin ligase function results in aberrant AMP-activated protein kinase (AMPK) activation and elongated primary cilia, which suggests a functional connection to cilia. Here, we reveal that the GID complex is an integral part of the cilium required for primary cilia-dependent signal transduction and the maintenance of ciliary protein homeostasis. We show that GID complex subunits localize to cilia in both Xenopus laevis and NIH3T3 cells. Furthermore, we report SHH signaling pathway defects that are independent of AMPK and mechanistic target of rapamycin (MTOR) activation. Despite correct localization of SHH signaling components at the primary cilium and functional GLI3 processing, we find a prominent reduction of some SHH signaling components in the cilium and a significant decrease in SHH target gene expression. Since our data reveal a critical function of the GID complex at the primary cilium, and because suppression of GID function in X. laevis results in ciliopathy-like phenotypes, we suggest that GID subunits are candidate genes for human ciliopathies that coincide with defects in SHH signal transduction.

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Yue, Yang, Martin F. Engelke, T. Lynne Blasius, and Kristen J. Verhey. "Hedgehog-induced ciliary trafficking of kinesin-4 motor KIF7 requires intraflagellar transport but not KIF7’s microtubule binding." Molecular Biology of the Cell 33, no. 1 (January 1, 2022). http://dx.doi.org/10.1091/mbc.e21-04-0215.

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Hedgehog pathway activation results in accumulation of kinesin-4 KIF7 and Gli transcription factors at the tip of the primary cilium. This article shows that intraflagellar transport driven by heterotrimeric kinesin-2 is required for KIF7’s ciliary accumulation, suggesting that signal-induced loading of intraflagellar transport trains occur in mammalian cells.

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Palla, Adelaida R., Keren I. Hilgendorf, Ann V. Yang, Jaclyn P. Kerr, Aaron C. Hinken, Janos Demeter, Peggy Kraft, et al. "Primary cilia on muscle stem cells are critical to maintain regenerative capacity and are lost during aging." Nature Communications 13, no. 1 (March 17, 2022). http://dx.doi.org/10.1038/s41467-022-29150-6.

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AbstractDuring aging, the regenerative capacity of muscle stem cells (MuSCs) decreases, diminishing the ability of muscle to repair following injury. We found that the ability of MuSCs to regenerate is regulated by the primary cilium, a cellular protrusion that serves as a sensitive sensory organelle. Abolishing MuSC cilia inhibited MuSC proliferation in vitro and severely impaired injury-induced muscle regeneration in vivo. In aged muscle, a cell intrinsic defect in MuSC ciliation was associated with the decrease in regenerative capacity. Exogenous activation of Hedgehog signaling, known to be localized in the primary cilium, promoted MuSC expansion, both in vitro and in vivo. Delivery of the small molecule Smoothened agonist (SAG1.3) to muscles of aged mice restored regenerative capacity leading to increased strength post-injury. These findings provide fresh insights into the signaling dysfunction in aged MuSCs and identify the ciliary Hedgehog signaling pathway as a potential therapeutic target to counter the loss of muscle regenerative capacity which accompanies aging.

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May, Elena A., Marian Kalocsay, Inès Galtier D’Auriac, Patrick S. Schuster, Steven P. Gygi, Maxence V. Nachury, and David U. Mick. "Time-resolved proteomics profiling of the ciliary Hedgehog response." Journal of Cell Biology 220, no. 5 (April 15, 2021). http://dx.doi.org/10.1083/jcb.202007207.

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The primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid, and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein–coupled receptor GPR161 in response to Hedgehog, and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the phosphatase Paladin as a cell type–specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.

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Smit, Marlinde J., Tosca E. I. Martini, Inna Armandari, Irena Bočkaj, Walderik W. Zomerman, Eduardo S. de Camargo Magalhães, Zillah Siragna, et al. "The developmental stage of the medulloblastoma cell-of-origin restricts Hedgehog pathway usage and drug sensitivity." Journal of Cell Science, May 10, 2022. http://dx.doi.org/10.1242/jcs.258608.

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Sonic Hedgehog (SHH) medulloblastoma originates from the cerebellar granule neuron progenitor (CGNP) lineage that depends on Hedgehog signaling for its perinatal expansion. While SHH tumors exhibit overall deregulation of this pathway, they also show patient age-specific aberrations. To investigate if the developmental stage of the CGNP can account for these age-specific lesions, we analyzed developing murine CGNP transcriptomes and observed highly dynamic gene expression as function of age. Cross-species comparison with human SHH medulloblastoma showed partial maintenance of these expression patterns, and highlighted low primary cilium expression as hallmark of infant medulloblastoma and early embryonic CGNPs. This coincided with reduced responsiveness to upstream Shh pathway component Smoothened, while sensitivity to downstream components Sufu and Gli was retained. Together, these findings can explain the preference for SUFU mutations in infant medulloblastoma and suggest that drugs targeting the downstream SHH pathway will be most appropriate for infant patients.

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Li, Weijun, Zhenhong Zhu, Kai He, Xiaoyu Ma, Robert J. Pignolo, Gary C. Sieck, Jinghua Hu, and Haitao Wang. "Primary cilia in satellite cells are the mechanical sensors for muscle hypertrophy." Proceedings of the National Academy of Sciences 119, no. 24 (June 7, 2022). http://dx.doi.org/10.1073/pnas.2103615119.

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Skeletal muscle atrophy is commonly associated with aging, immobilization, muscle unloading, and congenital myopathies. Generation of mature muscle cells from skeletal muscle satellite cells (SCs) is pivotal in repairing muscle tissue. Exercise therapy promotes muscle hypertrophy and strength. Primary cilium is implicated as the mechanical sensor in some mammalian cells, but its role in skeletal muscle cells remains vague. To determine mechanical sensors for exercise-induced muscle hypertrophy, we established three SC-specific cilium dysfunctional mouse models— Myogenic factor 5 ( Myf5 ) -Arf-like Protein 3 ( Arl3 ) −/− , Paired box protein Pax-7 ( Pax7 )- Intraflagellar transport protein 88 homolog ( Ift88 ) −/− , and Pax7-Arl3 −/− —by specifically deleting a ciliary protein ARL3 in MYF5-expressing SCs, or IFT88 in PAX7-expressing SCs, or ARL3 in PAX7-expressing SCs, respectively. We show that the Myf5-Arl3 −/− mice develop grossly the same as WT mice. Intriguingly, mechanical stimulation-induced muscle hypertrophy or myoblast differentiation is abrogated in Myf5-Arl3 −/− and Pax7-Arl3 −/− mice or primary isolated Myf5-Arl3 −/− and Pax7-Ift88 −/− myoblasts, likely due to defective cilia-mediated Hedgehog (Hh) signaling. Collectively, we demonstrate SC cilia serve as mechanical sensors and promote exercise-induced muscle hypertrophy via Hh signaling pathway.

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Yue, Shen, Liu-Ya Tang, Ying Tang, Yi Tang, Qiu-Hong Shen, Jie Ding, Yan Chen, et al. "Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception." eLife 3 (June 12, 2014). http://dx.doi.org/10.7554/elife.02555.

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Cell surface reception of Sonic hedgehog (Shh) must ensure that the graded morphogenic signal is interpreted accordingly in neighboring cells to specify tissue patterns during development. Here, we report endocytic sorting signals for the receptor Patched1 (Ptch1), comprising two ‘PPXY’ motifs, that direct it to degradation in lysosomes. These signals are recognized by two HECT-domain ubiquitin E3 ligases, Smurf1 and Smurf2, which are induced by Shh and become enriched in Caveolin-1 lipid rafts in association with Ptch1. Smurf-mediated endocytic turnover of Ptch1 is essential for its clearance from the primary cilium and pathway activation. Removal of both Smurfs completely abolishes the ability of Shh to sustain the proliferation of postnatal granule cell precursors in the cerebellum. These findings reveal a novel step in the Shh pathway activation as part of the Ptch1 negative feedback loop that precisely controls the signaling output in response to Shh gradient signal.

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Emechebe, Uchenna, Pavan Kumar P, Julian M. Rozenberg, Bryn Moore, Ashley Firment, Tooraj Mirshahi, and Anne M. Moon. "T-box3 is a ciliary protein and regulates stability of the Gli3 transcription factor to control digit number." eLife 5 (April 5, 2016). http://dx.doi.org/10.7554/elife.07897.

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Crucial roles for T-box3 in development are evident by severe limb malformations and other birth defects caused by T-box3 mutations in humans. Mechanisms whereby T-box3 regulates limb development are poorly understood. We discovered requirements for T-box at multiple stages of mouse limb development and distinct molecular functions in different tissue compartments. Early loss of T-box3 disrupts limb initiation, causing limb defects that phenocopy Sonic Hedgehog (Shh) mutants. Later ablation of T-box3 in posterior limb mesenchyme causes digit loss. In contrast, loss of anterior T-box3 results in preaxial polydactyly, as seen with dysfunction of primary cilia or Gli3-repressor. Remarkably, T-box3 is present in primary cilia where it colocalizes with Gli3. T-box3 interacts with Kif7 and is required for normal stoichiometry and function of a Kif7/Sufu complex that regulates Gli3 stability and processing. Thus, T-box3 controls digit number upstream of Shh-dependent (posterior mesenchyme) and Shh-independent, cilium-based (anterior mesenchyme) Hedgehog pathway function.

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Journal articles on the topic 'Mesothelioma, primary cilium, hedgehog pathway'

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