Ciliary signaling in stem cells in health and disease: Hedgehog pathway and beyond

Seminars in Cell & Developmental Biology - Tập 129 - Trang 115-125 - 2022
Issei S. Shimada1, Yoichi Kato1
1Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Azakawasumi, Mizuzho-cho, Mizuho-ku, Nagoya, 467-8601 Aichi, Japan

Tài liệu tham khảo

Mukhopadhyay, 2017, Trafficking to the primary cilium membrane, Mol. Biol. Cell., 28, 233, 10.1091/mbc.e16-07-0505 Sun, 2019, Three-dimensional architecture of epithelial primary cilia, Proc. Natl. Acad. Sci. U. S. A., 116, 9370, 10.1073/pnas.1821064116 Wilkinson, 2020, Haematopoietic stem cell self-renewal in vivo and ex vivo, Nat. Rev. Genet., 21, 541, 10.1038/s41576-020-0241-0 Comazzetto, 2021, Niches that regulate stem cells and hematopoiesis in adult bone marrow, Dev. Cell, 56, 1848, 10.1016/j.devcel.2021.05.018 Fuchs, 2020, Tissue stem cells: architects of their niches, Cell Stem Cell, 27, 532, 10.1016/j.stem.2020.09.011 May, 2021, Phosphorylation and ubiquitylation regulate protein trafficking, signaling, and the biogenesis of primary cilia, Front. Cell Dev. Biol., 9, 10.3389/fcell.2021.664279 Mick, 2015, Proteomics of primary cilia by proximity labeling, Dev. Cell., 35, 497, 10.1016/j.devcel.2015.10.015 Long, 2020, Transport of ciliary membrane proteins, Front. Cell Dev. Biol., 7, 381, 10.3389/fcell.2019.00381 Garcia-Gonzalo, 2017, Open Sesame: How transition fibers and the transition zone control ciliary composition, Cold Spring Harb. Perspect. Biol., 9, 10.1101/cshperspect.a028134 Reiter, 2017, Genes and molecular pathways underpinning ciliopathies, Nat. Rev. Mol. Cell Biol., 18, 533, 10.1038/nrm.2017.60 Bangs, 2017, Primary cilia and mammalian Hedgehog signaling, Cold Spring Harb. Perspect. Biol., 9, 10.1101/cshperspect.a028175 Raleigh, 2018, Cilia-associated oxysterols activate smoothened, Mol. Cell., 72, 10.1016/j.molcel.2018.08.034 Kim, 2009, Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus, Proc. Natl. Acad. Sci. U. S. A., 106, 21666, 10.1073/pnas.0912180106 Niewiadomski, 2014, Gli protein activity is controlled by multisite phosphorylation in vertebrate hedgehog signaling, Cell Rep., 6, 168, 10.1016/j.celrep.2013.12.003 Mukhopadhyay, 2013, The ciliary G-protein-coupled receptor Gpr161 negatively regulates the sonic hedgehog pathway via cAMP signaling, Cell, 152, 210, 10.1016/j.cell.2012.12.026 Bachmann, 2016, Gpr161 anchoring of PKA consolidates GPCR and cAMP signaling, Proc. Natl. Acad. Sci. U. S. A., 113, 7786, 10.1073/pnas.1608061113 Matissek, 2020, GLI3: A mediator of genetic diseases, development and cancer, Cell Commun. Signal., 18, 10.1186/s12964-020-00540-x Shimada, 2018, Basal suppression of the sonic hedgehog pathway by the G-protein-coupled receptor Gpr161 restricts medulloblastoma pathogenesis, Cell Rep., 22, 10.1016/j.celrep.2018.01.018 Shimada, 2019, Derepression of sonic hedgehog signaling upon Gpr161 deletion unravels forebrain and ventricular abnormalities, Dev. Biol., 450, 47, 10.1016/j.ydbio.2019.03.011 Hwang, 2018, The G protein-coupled receptor Gpr161 regulates forelimb formation, limb patterning and skeletal morphogenesis in a primary cilium-dependent manner, Dev, 145 Hwang, 2021, Ciliary and extraciliary gpr161 pools repress hedgehog signaling in a tissue-specific manner, Elife, 10, 10.7554/eLife.67121 Badgandi, 2017, Tubby family proteins are adapters for ciliary trafficking of integral membrane proteins, J. Cell Biol., 216, 10.1083/jcb.201607095 Vasquez, 2021, An updated SYSCILIA gold standard (SCGSv2) of known ciliary genes, revealing the vast progress that has been made in the cilia research field, Mol. Biol. Cell., 10.1091/mbc.E21-05-0226 Schou, 2015, Ins and outs of GPCR signaling in primary cilia, EMBO Rep., 16, 1099, 10.15252/embr.201540530 Omori, 2015, Identification of G protein-coupled receptors (GPCRs) in primary cilia and their possible involvement in body weight control, PLoS One, 10, 10.1371/journal.pone.0128422 Mukhopadhyay, 2010, TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia, Genes Dev., 24, 2180, 10.1101/gad.1966210 Legué, 2019, Tulp3 is a ciliary trafficking gene that regulates polycystic kidney disease, Curr. Biol., 29, 10.1016/j.cub.2019.01.054 Hwang, 2019, Tulp3 regulates renal cystogenesis by trafficking of cystoproteins to cilia, Curr. Biol., 29, 10.1016/j.cub.2019.01.047 Legué, 2020, Mutations in ciliary trafficking genes affect sonic hedgehog-dependent neural tube patterning differentially along the anterior–posterior axis, Neuroscience, 450, 3, 10.1016/j.neuroscience.2020.07.015 Cameron, 2009, Tulp3 is a critical repressor of Mouse hedgehog signaling, Dev. Dyn., 238, 1140, 10.1002/dvdy.21926 Tran, 2008, THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia, Nat. Genet., 40, 403, 10.1038/ng.105 Fansa, 2016, Sorting of lipidated cargo by the Arl2/Arl3 system, Small GTPases, 7, 222, 10.1080/21541248.2016.1224454 Caspary, 2007, The graded response to sonic hedgehog depends on cilia architecture, Dev. Cell., 12, 767, 10.1016/j.devcel.2007.03.004 Cantagrel, 2008, Mutations in the cilia gene ARL13B lead to the classical form of joubert syndrome, Am. J. Hum. Genet., 83, 170, 10.1016/j.ajhg.2008.06.023 Gotthardt, 2015, A G-protein activation cascade from Arl13B to Arl3 and implications for ciliary targeting of lipidated proteins, Elife, 4, 10.7554/eLife.11859 Humbert, 2012, ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting, Proc. Natl. Acad. Sci. U. S. A., 109, 19691, 10.1073/pnas.1210916109 Wright, 2011, An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium, Genes Dev., 25, 2347, 10.1101/gad.173443.111 Resh, 2013, Covalent lipid modifications of proteins, Curr. Biol., 23, 10.1016/j.cub.2013.04.024 Grayson, 2002, Localization in the human retina of the X-linked retinitis pigmentosa protein RP2, its homologue cofactor C and the RP2 interacting protein ARl3, Hum. Mol. Genet, 11, 3065, 10.1093/hmg/11.24.3065 Mariani, 2016, Arl13b regulates Shh signaling from both inside and outside the cilium, Mol. Biol. Cell., 27, 3780, 10.1091/mbc.e16-03-0189 Gigante, 2020, Arl13b regulates sonic hedgehog signaling from outside primary cilia, Elife, 9, 10.7554/eLife.50434 Falkenburger, 2010, Phosphoinositides: lipid regulators of membrane proteins, J. Physiol., 588, 3179, 10.1113/jphysiol.2010.192153 Kong, 2000, Cloning and characterization of a 72-kDa inositol-polyphosphate 5-phosphatase localized to the Golgi network, J. Biol. Chem., 275, 24052, 10.1074/jbc.M000874200 Kisseleva, 2000, The isolation and characterization of a cDNA encoding phospholipid- specific inositol polyphosphate 5-phosphatase, J. Biol. Chem., 275, 20110, 10.1074/jbc.M910119199 Chávez, 2015, Modulation of ciliary phosphoinositide content regulates trafficking and sonic hedgehog signaling output, Dev. Cell., 34, 338, 10.1016/j.devcel.2015.06.016 Garcia-Gonzalo, 2015, Phosphoinositides regulate ciliary protein trafficking to modulate Hedgehog signaling, Dev. Cell., 34, 400, 10.1016/j.devcel.2015.08.001 Dyson, 2017, INPP5E regulates phosphoinositide-dependent cilia transition zone function, J. Cell Biol., 216, 247, 10.1083/jcb.201511055 Constable, 2020, The ciliary phosphatidylinositol phosphatase Inpp5e plays positive and negative regulatory roles in Shh signaling, Development, 147 Delling, 2013, Primary cilia are specialized calcium signalling organelles, Nature, 504, 311, 10.1038/nature12833 Decaen, 2013, Direct recording and molecular identification of the calcium channel of primary cilia, Nature, 504, 315, 10.1038/nature12832 DeCaen, 2016, Atypical calcium regulation of the PKD2-L1 polycystin ion channel, Elife, 5, 10.7554/eLife.13413 Moore, 2016, Cilia have high cAMP levels that are inhibited by Sonic Hedgehog-regulated calcium dynamics, Proc. Natl. Acad. Sci. U. S. A., 113, 13069, 10.1073/pnas.1602393113 Nauli, 2003, Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells, Nat. Genet., 33, 129, 10.1038/ng1076 Du, 2021, Restoration of proximal tubule flow–activated transport prevents cyst growth in polycystic kidney disease, JCI Insight, 6, 10.1172/jci.insight.146041 Delling, 2016, Primary cilia are not calcium-responsive mechanosensors, Nature, 531, 656, 10.1038/nature17426 Mizuno, 2020, Role of Ca2+ transients at the node of the mouse embryo in breaking of left-right symmetry, Sci. Adv., 6, 10.1126/sciadv.aba1195 Bangs, 2015, Lineage specificity of primary cilia in the mouse embryo, Nat. Cell Biol., 17, 113, 10.1038/ncb3091 Takao, 2013, Asymmetric distribution of dynamic calcium signals in the node of mouse embryo during left-right axis formation, Dev. Biol., 376, 23, 10.1016/j.ydbio.2013.01.018 Piotrowska-Nitsche, 2012, Live imaging of individual cell divisions in mouse neuroepithelium shows asymmetry in cilium formation and Sonic hedgehog response, Cilia, 1, 10.1186/2046-2530-1-6 Besschetnova, 2010, Identification of signaling pathways regulating primary cilium length and flow-mediated adaptation, Curr. Biol., 20, 182, 10.1016/j.cub.2009.11.072 Hansen, 2020, Nanobody-directed targeting of optogenetic tools to study signaling in the primary cilium, Elife, 9, 1, 10.7554/eLife.57907 Jiang, 2019, Direct visualization of cAMP signaling in primary cilia reveals up-regulation of ciliary GPCR activity following Hedgehog activation, Proc. Natl. Acad. Sci. U. S. A., 116, 12066, 10.1073/pnas.1819730116 Truong, 2021, Vertebrate cells differentially interpret ciliary and extraciliary cAMP, Cell, 184, 10.1016/j.cell.2021.04.002 Shimada, 2017, G-protein-coupled receptor signaling and neural tube closure defects, Birth Defects Res, 109, 129, 10.1002/bdra.23567 Lepanto, 2016, Neuron’s little helper: the role of primary cilia in neurogenesis, Neurogenesis, 3, 10.1080/23262133.2016.1253363 Silva-Vargas, 2016, Age-dependent niche signals from the choroid plexus regulate adult neural stem cells, Cell Stem Cell, 19, 643, 10.1016/j.stem.2016.06.013 Brooks, 2020, Sonic hedgehog signaling directs patterned cell remodeling during cranial neural tube closure, Elife, 9, 1, 10.7554/eLife.60234 Pal, 2015, Primary cilium and sonic hedgehog signaling during neural tube patterning: role of GPCRs and second messengers, Dev. Neurobiol., 75, 337, 10.1002/dneu.22193 Hwang, 2015, G-protein-coupled receptors and localized signaling in the primary cilium during ventral neural tube patterning, Birth Defects Res. Part A - Clin. Mol. Teratol., 103, 12, 10.1002/bdra.23267 Tuson, 2011, Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube, Development, 138, 4921, 10.1242/dev.070805 May, 2021, Time-resolved proteomics profiling of the ciliary Hedgehog response, J. Cell Biol., 220, 10.1083/jcb.202007207 Vuolo, 2015, Ciliary adenylyl cyclases control the Hedgehog pathway, J. Cell Sci., 128, 2928 Somatilaka, 2020, Ankmy2 prevents smoothened-independent hyperactivation of the hedgehog pathway via cilia-regulated adenylyl cyclase signaling, Dev. Cell., 54, 10.1016/j.devcel.2020.06.034 Das, 2014, Apical abscission alters cell polarity and dismantles the primary cilium during neurogenesis, Science, 343, 200, 10.1126/science.1247521 Toro-Tapia, 2020, Primary cilium remodeling mediates a cell signaling switch in differentiating neurons, Sci. Adv., 6, 10.1126/sciadv.abb0601 Kasioulis, 2017, Inter-dependent apical microtubule and actin dynamics orchestrate centrosome retention and neuronal delamination, Elife, 6, 10.7554/eLife.26215 Penisson, 2019, Genes and mechanisms involved in the generation and amplification of basal radial glial cells, Front. Cell. Neurosci., 13 Hasenpusch-Theil, 2021, The multifaceted roles of primary cilia in the development of the cerebral cortex, Front. Cell Dev. Biol., 9, 86, 10.3389/fcell.2021.630161 Chau, 2015, Progressive differentiation and instructive capacities of amniotic fluid and cerebrospinal fluid proteomes following neural tube closure, Dev. Cell., 35, 789, 10.1016/j.devcel.2015.11.015 Lehtinen, 2011, The cerebrospinal fluid provides a proliferative niche for neural progenitor cells, Neuron, 69, 893, 10.1016/j.neuron.2011.01.023 Paridaen, 2013, XAsymmetric inheritance of centrosome-associated primary cilium membrane directs ciliogenesis after cell division, Cell, 155, 333, 10.1016/j.cell.2013.08.060 Wilsch-Bräuninger, 2012, Basolateral rather than apical primary cilia on neuroepithelial cells committed to delamination, Development, 139, 95, 10.1242/dev.069294 Guo, 2015, Developmental disruptions underlying brain abnormalities in ciliopathies, Nat. Commun., 6, 10.1038/ncomms8857 Wilson, 2012, Primary cilia and Gli3 activity regulate cerebral cortical size, Dev. Neurobiol., 72, 1196, 10.1002/dneu.20985 Snedeker, 2017, Unique spatiotemporal requirements for intraflagellar transport genes during forebrain development, PLoS One, 12, 10.1371/journal.pone.0173258 Spassky, 2008, Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool, Dev. Biol., 317, 246, 10.1016/j.ydbio.2008.02.026 Foerster, 2017, MTORC1 signaling and primary cilia are required for brain ventricle morphogenesis, Development, 144, 201 Ocbina, 2011, Complex interactions between genes controlling trafficking in primary cilia, Nat. Genet., 43, 547, 10.1038/ng.832 Yabut, 2015, Suppressor of fused is critical for maintenance of neuronal progenitor identity during corticogenesis, Cell Rep., 12, 2021, 10.1016/j.celrep.2015.08.031 Yabut, 2020, The neocortical progenitor specification program is established through combined modulation of SHH and FGF signaling, J. Neurosci., 40, 6872, 10.1523/JNEUROSCI.2888-19.2020 Wang, 2016, Hedgehog signaling promotes basal progenitor expansion and the growth and folding of the neocortex, Nat. Neurosci., 19, 888, 10.1038/nn.4307 Andreu-Cervera, 2021, Cilia, ciliopathies and hedgehog-related forebrain developmental disorders, Neurobiol. Dis., 150, 10.1016/j.nbd.2020.105236 Higginbotham, 2013, Arl13b-regulated cilia activities are essential for polarized radial glial scaffold formation, Nat. Neurosci., 16, 1000, 10.1038/nn.3451 Matsumoto, 2019, Dynamic changes in ultrastructure of the primary cilium in migrating neuroblasts in the postnatal brain, J. Neurosci., 39, 9967, 10.1523/JNEUROSCI.1503-19.2019 Stoufflet, 2020, Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration, Sci. Adv., 6, 10.1126/sciadv.aba3992 Guo, 2019, Primary cilia signaling promotes axonal tract development and is disrupted in joubert syndrome-related disorders models, Dev. Cell., 51, 10.1016/j.devcel.2019.11.005 Kim, 2021, Wnt1 lineage specific deletion of Gpr161 results in embryonic midbrain malformation and failure of craniofacial skeletal development, Front. Genet, 0, 2366 Hasenpusch-Theil, 2020, A transient role of the ciliary gene inpp5e in controlling direct versus indirect neurogenesis in cortical development, Elife, 9, 1, 10.7554/eLife.58162 Sathyanesan, 2019, Emerging connections between cerebellar development, behaviour and complex brain disorders, Nat. Rev. Neurosci., 20, 298, 10.1038/s41583-019-0152-2 Chizhikov, 2007, Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool, J. Neurosci., 27, 9780, 10.1523/JNEUROSCI.5586-06.2007 Lewis, 2004, Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum, Dev. Biol., 270, 393, 10.1016/j.ydbio.2004.03.007 Kaushansky, 2006, Lineage-specific hematopoietic growth factors, N. Engl. J. Med., 354, 2034, 10.1056/NEJMra052706 Singh, 2016, Primary cilia are present on human blood and bone marrow cells and mediate Hedgehog signaling, Exp. Hematol., 44, 10.1016/j.exphem.2016.08.009 Liu, 2019, Primary cilia regulate hematopoietic stem and progenitor cell specification through Notch signaling in zebrafish, Nat. Commun., 10 Zhao, 2009, Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia, Nature, 458, 776, 10.1038/nature07737 Trowbridge, 2006, Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration, Proc. Natl. Acad. Sci. U. S. A., 103, 14134, 10.1073/pnas.0604568103 Scheffold, 2020, Elevated Hedgehog activity contributes to attenuated DNA damage responses in aged hematopoietic cells, Leukemia, 34, 1125, 10.1038/s41375-019-0641-3 Hofmann, 2009, Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis, Cell Stem Cell, 4, 559, 10.1016/j.stem.2009.03.016 Gao, 2009, Hedgehog signaling is dispensable for adult hematopoietic stem cell function, Cell Stem Cell, 4, 548, 10.1016/j.stem.2009.03.015 Hsu, 2014, Transit-amplifying cells orchestrate stem cell activity and tissue regeneration, Cell, 157, 935, 10.1016/j.cell.2014.02.057 Woo, 2012, Shh maintains dermal papilla identity and hair morphogenesis via a Noggin-Shh regulatory loop, Genes Dev., 26, 1235, 10.1101/gad.187401.112 Lehman, 2009, An essential role for dermal primary cilia in hair follicle morphogenesis, J. Invest. Dermatol., 129, 438, 10.1038/jid.2008.279 Chen, 2015, The ciliopathy gene rpgrip1l is essential for hair follicle development, J. Invest. Dermatol., 135, 701, 10.1038/jid.2014.483 Croyle, 2011, Role of epidermal primary cilia in the homeostasis of skin and hair follicles, Development, 138, 1675, 10.1242/dev.060210 Shwartz, 2020, Cell types promoting goosebumps form a niche to regulate hair follicle stem cells, Cell, 182, 10.1016/j.cell.2020.06.031 Peterson, 2015, Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches, Cell Stem Cell, 16, 400, 10.1016/j.stem.2015.02.006 Serra, 2008, Role of intraflagellar transport and primary cilia in skeletal development, Anat. Rec., 291, 1049, 10.1002/ar.20634 Amano, 2015, Conditional deletion of indian hedgehog in limb mesenchyme results in complete loss of growth plate formation but allows mature osteoblast differentiation, J. Bone Miner. Res., 30, 2262, 10.1002/jbmr.2582 Maeda, 2007, Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone, Proc. Natl. Acad. Sci. U. S. A., 104, 6382, 10.1073/pnas.0608449104 Shi, 2021, Gli1+ progenitors mediate bone anabolic function of teriparatide via Hh and Igf signaling, Cell Rep., 36, 10.1016/j.celrep.2021.109542 Zhao, 2015, The suture provides a niche for mesenchymal stem cells of craniofacial bones, Nat. Cell Biol., 17, 386, 10.1038/ncb3139 Shi, 2017, Gli1 identifies osteogenic progenitors for bone formation and fracture repair, Nat. Commun., 8, 10.1038/s41467-017-02171-2 Xiao, 2006, Cilia-like structures and polycystin-1 in osteoblasts/osteocytes and associated abnormalities in skeletogenesis and Runx2 expression, J. Biol. Chem., 281, 30884, 10.1074/jbc.M604772200 Boulter, 2001, Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene, Proc. Natl. Acad. Sci. U. S. A., 98, 12174, 10.1073/pnas.211191098 Qiu, 2012, Conditional mesenchymal disruption of Pkd1 results in osteopenia and polycystic kidney disease, PLoS One, 7, 10.1371/journal.pone.0046038 Xiao, 2010, Conditional disruption of Pkd1 in osteoblasts results in osteopenia due to direct impairment of bone formation, J. Biol. Chem., 285, 1177, 10.1074/jbc.M109.050906 Hofherr, 2011, TRPP channels and polycystins, Adv. Exp. Med. Biol., Adv. Exp. Med. Biol., 287, 10.1007/978-94-007-0265-3_16 Talbot, 2014, The cleaved cytoplasmic tail of polycystin-1 regulates Src-dependent STAT3 activation, J. Am. Soc. Nephrol., 25, 1737, 10.1681/ASN.2013091026 Xiao, 2018, Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis, J. Clin. Invest., 128, 157, 10.1172/JCI93725 Merrick, 2019, Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ, Hum. Mol. Genet, 28, 16, 10.1093/hmg/ddy322 Visvader, 2016, Tissue-specific designs of stem cell hierarchies, Nat. Cell Biol., 18, 349, 10.1038/ncb3332 Guen, 2017, EMT programs promote basal mammary stem cell and tumor-initiating cell stemness by inducing primary ciliogenesis and Hedgehog signaling, Proc. Natl. Acad. Sci. U. S. A., 114, E10532, 10.1073/pnas.1711534114 McDermott, 2010, Primary cilia regulate branching morphogenesis during mammary gland development, Curr. Biol., 20, 731, 10.1016/j.cub.2010.02.048 Mitchell, 2014, Normal mammary development and function in mice with Ift88 deleted in MMTV- and K14-Cre expressing cells, Cilia, 3, 10.1186/2046-2530-3-4 Li, 2008, Reciprocal intraepithelial interactions between TP63 and Hedgehog signaling regulate quiescence and activation of progenitor elaboration by mammary stem cells, Stem Cells, 26, 1253, 10.1634/stemcells.2007-0691 Prager, 2019, Cancer stem cells: the architects of the tumor ecosystem, Cell Stem Cell, 24, 41, 10.1016/j.stem.2018.12.009 Plaks, 2015, The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells?, Cell Stem Cell, 16, 225, 10.1016/j.stem.2015.02.015 Juraschka, 2019, Medulloblastoma in the age of molecular subgroups: a review: JNSPG 75th Anniversary invited review article, J. Neurosurg. Pedia, 24, 353, 10.3171/2019.5.PEDS18381 Han, 2009, Dual and opposing roles of primary cilia in medulloblastoma development, Nat. Med., 15, 1062, 10.1038/nm.2020 Conduit, 2017, A compartmentalized phosphoinositide signaling axis at cilia is regulated by INPP5E to maintain cilia and promote Sonic Hedgehog medulloblastoma, Oncogene, 36, 5969, 10.1038/onc.2017.208 Bay, 2018, Disruption of the ciliary GTPase Arl13b suppresses Sonic hedgehog overactivation and inhibits medulloblastoma formation, Proc. Natl. Acad. Sci. U. S. A., 115, 1570, 10.1073/pnas.1706977115 Yin, 2019, Dual regulatory functions of SUFU and targetome of GLI2 in SHH subgroup medulloblastoma, Dev. Cell., 48, 10.1016/j.devcel.2018.11.015 Flora, 2009, Deletion of Atoh1 disrupts sonic hedgehog signaling in the developing cerebellum and prevents medulloblastoma, Science, 326, 1424, 10.1126/science.1181453 Klisch, 2017, Jak2-mediated phosphorylation of atoh1 is critical for medulloblastoma growth, Elife, 6, 10.7554/eLife.31181 Ayrault, 2010, Atoh1 inhibits neuronal differentiation and collaborates with Gli1 to generate medulloblastoma-initiating cells, Cancer Res, 70, 5618, 10.1158/0008-5472.CAN-09-3740 Forget, 2014, Shh signaling protects atoh1 from degradation mediated by the E3Ubiquitin ligase Huwe1 in neural precursors, Dev. Cell., 29, 649, 10.1016/j.devcel.2014.05.014 Chang, 2019, Atoh1 controls primary cilia formation to allow for SHH-triggered granule neuron progenitor proliferation, Dev. Cell., 48, 10.1016/j.devcel.2018.12.017 Wong, 2009, Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis, Nat. Med., 15, 1055, 10.1038/nm.2011 Eguether, 2018, Mixed signals from the cell’s antennae: primary cilia in cancer, EMBO Rep., 19, 10.15252/embr.201846589 Pitt, 2015, CXCL12-producing vascular endothelial niches control acute T Cell leukemia maintenance, Cancer Cell, 27, 755, 10.1016/j.ccell.2015.05.002 Lim, 2015, Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia, Sci. Transl. Med., 7, 10.1126/scitranslmed.aaa5731 Lau, 2019, Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity, Oncogene, 38, 687, 10.1038/s41388-018-0431-9 Chaudhry, 2017, GLI3 repressor determines Hedgehog pathway activation and is required for response to SMO antagonist glasdegib in AML, Blood, 129, 3465, 10.1182/blood-2016-05-718585 Burns, 2018, Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia, Leukemia, 32, 2126, 10.1038/s41375-018-0097-x Tharmapalan, 2019, Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention, EMBO J., 38, 10.15252/embj.2018100852 Menzl, 2014, Loss of primary cilia occurs early in breast cancer development, Cilia, 3, 10.1186/2046-2530-3-7 Légaré, 2017, SPEN, a new player in primary cilia formation and cell migration in breast cancer, Breast Cancer Res, 19, 10.1186/s13058-017-0897-3 Kim, 2015, Nek2 activation of Kif24 ensures cilium disassembly during the cell cycle, Nat. Commun., 6 Feigin, 2014, G-protein-coupled receptor GPR161 is overexpressed in breast cancer and is a promoter of cell proliferation and invasion, Proc. Natl. Acad. Sci. U. S. A., 111, 4191, 10.1073/pnas.1320239111 Ezratty, 2011, A role for the primary cilium in notch signaling and epidermal differentiation during skin development, Cell, 145, 1129, 10.1016/j.cell.2011.05.030 Nakagawa, 2017, APC sets the Wnt tone necessary for cerebral cortical progenitor development, Genes Dev., 31, 1679, 10.1101/gad.302679.117 Marley, 2013, GPR88 reveals a discrete function of primary cilia as selective insulators of GPCR cross-talk, PLoS One, 8, 10.1371/journal.pone.0070857 Berbari, 2008, Identification of ciliary localization sequences within the third intracellular loop of G protein-coupled receptors, Mol. Biol. Cell., 19, 1540, 10.1091/mbc.e07-09-0942 Loktev, 2013, Neuropeptide Y family receptors traffic via the bardet-biedl syndrome pathway to signal in neuronal primary cilia, Cell Rep., 5, 1316, 10.1016/j.celrep.2013.11.011 Koemeter-Cox, 2014, Primary cilia enhance kisspeptin receptor signaling on gonadotropin- releasing hormone neurons, Proc. Natl. Acad. Sci. U. S. A., 111, 10335, 10.1073/pnas.1403286111 Walker, 2019, Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model, Nat. Commun., 10, 10.1038/s41467-019-12067-y