Skip to main content

Advertisement

Log in

Sonic hedgehog patterning during cerebellar development

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The morphogenic factor sonic hedgehog (Shh) actively orchestrates many aspects of cerebellar development and maturation. During embryogenesis, Shh signaling is active in the ventricular germinal zone (VZ) and represents an essential signal for proliferation of VZ-derived progenitors. Later, Shh secreted by Purkinje cells sustains the amplification of postnatal neurogenic niches: the external granular layer and the prospective white matter, where excitatory granule cells and inhibitory interneurons are produced, respectively. Moreover, Shh signaling affects Bergmann glial differentiation and promotes cerebellar foliation during development. Here we review the most relevant functions of Shh during cerebellar ontogenesis, underlying its role in physiological and pathological conditions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Simpson F, Kerr MC, Wicking C (2009) Trafficking, development and hedgehog. Mech Dev 126(5–6):279–288

    Article  PubMed  CAS  Google Scholar 

  2. Tashiro S, Michiue T, Higashijima S, Zenno S, Ishimaru S, Takahashi F, Orihara M, Kojima T, Saigo K (1993) Structure and expression of hedgehog, a Drosophila segment-polarity gene required for cell–cell communication. Gene 124(2):183–189

    Article  PubMed  CAS  Google Scholar 

  3. Nüsslein-Volhard C, Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287(5785):795–801

    Article  PubMed  Google Scholar 

  4. Martinez-Arias A, Lawrence PA (1985) Parasegments and compartments in the Drosophila embryo. Nature 313(6004):639–642

    Article  PubMed  CAS  Google Scholar 

  5. Wada H, Makabe K (2006) Genome duplications of early vertebrates as a possible chronicle of the evolutionary history of the neural crest. Int J Biol Sci 2(3):133–141

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Chang DT, Lopez A, von Kessler DP, Chiang C, Simandl BK, Zhao R, Seldin MF, Fallon JF, Beachy PA (1994) Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development 120(11):3339–3353

    PubMed  CAS  Google Scholar 

  7. Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP (1993) Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75(7):1417–1430

    Article  PubMed  CAS  Google Scholar 

  8. Machold R, Fishell G (2002) Hedgehog patterns midbrain architecture. Trends Neurosci 25(1):10–11

    Article  PubMed  CAS  Google Scholar 

  9. Fuccillo M, Joyner AL, Fishell G (2006) Morphogen to mitogen: the multiple roles of hedgehog signaling in vertebrate neural development. Nat Rev Neurosci 7(10):772–783

    Article  PubMed  CAS  Google Scholar 

  10. Yam PT, Charron F (2013) Signaling mechanisms of non-conventional axon guidance cues: the Shh, BMP and Wnt morphogens. Curr Opin Neurobiol 23(6):965–973

    Article  PubMed  CAS  Google Scholar 

  11. Vaillant C, Monard D (2009) SHH pathway and cerebellar development. Cerebellum 8(3):291–301

    Article  PubMed  Google Scholar 

  12. Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY (2006) A protein–protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 125(4):801–814

    Article  PubMed  CAS  Google Scholar 

  13. Bale AE (2002) Hedgehog signaling and human disease. Annu Rev Genomics Hum Genet 3:47–65

    Article  PubMed  CAS  Google Scholar 

  14. Teglund S, Toftgard R (1805) Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta 2:181–208

    Google Scholar 

  15. Varjosalo M, Taipale J (2008) Hedgehog: functions and mechanisms. Genes Dev 22(18):2454–2472

    Article  PubMed  CAS  Google Scholar 

  16. Aguilar A, Meunier A, Strehl L, Martinovic J, Bonniere M, Attie-Bitach T, Encha-Razavi F, Spassky N (2012) Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome. Proc Natl Acad Sci USA 109(42):16951–16956

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Millen KL, Gleeson JG (2008) Cerebellar development and disease. Curr Opin Neurobiol 18(1):12–19

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Barakat MT, Humke EW, Scott MP (2013) Kif3a is necessary for initiation and maintenance of medulloblastoma. Carcinogenesis 34(6):1382–1392

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Porter JA, Young KE, Beachy PA (1996) Cholesterol modification of hedgehog signaling proteins in animal development. Science 274(5285):255–259

    Article  PubMed  CAS  Google Scholar 

  20. Cohen MM Jr (2004) The hedgehog signaling network. Am J Med Genet A 123A(1):5–28. Erratum in: Am J Med Genet (2004) 124A(4):439–440

  21. Chamoun Z, Mann RK, Nellen D, von Kessler DP, Bellotto M, Beachy PA, Basler K (2001) Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science 293(5537):2080–2084

    Article  PubMed  CAS  Google Scholar 

  22. Lee JJ, Ekker SC, von Kessler DP, Porter JA, Sun BI, Beachy PA (1994) Autoproteolysis in hedgehog protein biogenesis. Science 266(5190):1528–1537

    Article  PubMed  CAS  Google Scholar 

  23. Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, Ambrose CM, Garber EA, Miatkowski K et al (1998) Identification of a palmitic acid-modified form of human sonic hedgehog. J Biol Chem 273(22):14037–14045

    Article  PubMed  CAS  Google Scholar 

  24. Lewis PM, Dunn MP, McMahon JA, Logan M, Martin JF, St-Jacques B, McMahon AP (2001) Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 105(5):599–612

    Article  PubMed  CAS  Google Scholar 

  25. Wang Y, McMahon AP, Allen BL (2007) Shifting paradigms in Hedgehog signaling. Curr Opin Cell Biol 19(2):159–165

    Article  PubMed  CAS  Google Scholar 

  26. Goetz A, Suber LM, Scott WJ Jr, Schreiner CM, Robbins DJ (2001) A freely diffusible form of sonic hedgehog mediates long-range signaling. Nature 411(6838):716–720

    Article  PubMed  Google Scholar 

  27. Chen MH, Li YJ, Kawakami T, Xu SM, Chuang PT (2004) Palmitoylation is required for the production of a soluble multimeric hedgehog protein complex and long-range signaling in vertebrates. Genes Dev 18(6):641–659

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Fico A, Maina F, Dono R (2011) Fine-tuning of cell signaling by glypicans. Cell Mol Life Sci 68(6):923–929

    Article  PubMed  CAS  Google Scholar 

  29. Gritli-Linde A, Lewis P, McMahon AP, Linde A (2001) The whereabouts of a morphogen: direct evidence for short- and graded long-range activity of hedgehog signaling peptides. Dev Biol 236(2):364–386

    Article  PubMed  CAS  Google Scholar 

  30. McCarthy RA, Barth JL, Chintalapudi MR, Knaak C, Argraves WS (2002) Megalin functions as an endocytic sonic hedgehog receptor. J Biol Chem 277(28):25660–25667

    Article  PubMed  CAS  Google Scholar 

  31. Litingtung Y, Chiang C (2000) Control of Shh activity and signaling in the neural tube. Dev Dyn 219(2):143–154

    Article  PubMed  CAS  Google Scholar 

  32. Izzi L, Lévesque M, Morin S, Laniel D, Wilkes BC, Mille F, Krauss RS, McMahon AP, Allen BL, Charron F (2011) Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation. Dev Cell 20(6):788–801

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Marigo V, Davey RA, Zuo Y, Cunningham JM, Tabin CJ (1996) Biochemical evidence that patched is the hedgehog receptor. Nature 384(6605):176–179

    Article  PubMed  CAS  Google Scholar 

  34. Kang JS, Zhang W, Krauss RS (2007) Hedgehog signaling: cooking with Gas1. Sci STKE 403:pe50

  35. Taipale J, Cooper MK, Maiti T, Beachy PA (2002) Patched acts catalytically to suppress the activity of Smoothened. Nature 418(6900):892–897

    Article  PubMed  CAS  Google Scholar 

  36. Chen Y, Sasai N, Ma G, Yue T, Jia J, Briscoe J, Jiang J (2011) Sonic hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of smoothened. PLoS Biol 9(6):e1001083

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Cohen MM Jr (2010) Hedgehog signaling update. Am J Med Genet A 152A(8):1875–1914

    Article  PubMed  CAS  Google Scholar 

  38. Goetz SC, Anderson KV (2010) The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11(5):331–344

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Spassky N, Han YG, Agular A, Strehl L, Besse L, Laclef C, Ros MR, Garcia Verdugo JM, Alvarez-Buylla A (2008) Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool. Dev Biol 317(1):246–259

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Chizhikov VV, Davenport J, Zhang Q, Shih EK, Cabello OA, Fuchs JL, Yoder BK, Millen KJ (2007) Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. J Neurosci 27(36):9780–9789

    Article  PubMed  CAS  Google Scholar 

  41. Merchant M, Vajdos FF, Ultsch M, Maun HR, Wendt U, Cannon J, Desmarais W, Lazarus RA, de Vos AM, de Sauvage FJ (2004) Suppressor of fused regulates Gli activity through a dual binding mechanism. Mol Cell Biol 24(19):8627–8641

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Svärd J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergström A, Ericson J, Toftgård R, Teglund S (2006) Genetic elimination of suppressor of fused reveals an essential repressor function in the mammalian hedgehog signaling pathway. Dev Cell 10(2):187–197

    Article  PubMed  CAS  Google Scholar 

  43. Chen MH, Gao N, Kawakami T, Chuang PT (2005) Mice deficient in the fused homolog do not exhibit phenotypes indicative of perturbed hedgehog signaling during embryonic development. Mol Cell Biol 25(16):7042–7053

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Merchant M, Evangelista M, Luoh SM, Frantz GD, Chalasani S, Carano RA, van Hoy M, Raminez J, Ogasawara AK, McFarland LM et al (2005) Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol Cell Biol 25(16):7054–7068

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  45. Wang B, Fallon JF, Beachy PA (2000) Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100(4):423–434

    Article  PubMed  CAS  Google Scholar 

  46. Pan Y, Bai CB, Joyner AL, Wang B (2006) Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol 26(9):3365–3377

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Zhang Q, Zhang L, Wang B, Ou CY, Chien CT, Jiang J (2006) A hedgehog-induced BTB protein modulates hedgehog signaling by degrading Ci/Gli transcription factor. Dev Cell 10(6):719–729

    Article  PubMed  CAS  Google Scholar 

  48. Pan Y, Wang B (2007) A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome. J Biol Chem 282(15):10846–10852

    Article  PubMed  CAS  Google Scholar 

  49. Lelievre V, Seksenyan A, Nobuta H, Yong WH, Chhith S, Niewiadomski P, Cohen JR, Dong H, Flores A, Liau LM, Kornblum HI, Scott MP, Wascheck JA (2008) Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice. Dev Biol 313(1):359–370

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Niewiadomski P, Zhujiang A, Youssef M, Waschek JA (2013) Interaction of PACAP with sonic hedgehog reveals complex regulation of the hedgehog pathway by PKA. Cell Signal 25(11):2222–2230

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15(23):3059–3087

    Article  PubMed  CAS  Google Scholar 

  52. Tukachinsky H, Lopez LV, Salic A (2010) A mechanism for vertebrate hedgehog signaling: recruitment to cilia and dissociation of SuFu–Gli protein complexes. J Cell Biol 191(2):415–428

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Oliver TG, Grasfeder LL, Carroll AL, Kaiser C, Gillingham CL, Lin SM, Wickramasinghe R, Scott MP, Wechsler-Reya RJ (2003) Transcriptional profiling of the sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci USA 100(12):7331–7336

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. Pierani A, Brenner-Morton S, Chiang C, Jessell TM (1999) A sonic hedgehog-independent, retinoid-activated pathway of neurogenesis in the ventral spinal cord. Cell 97(7):903–915

    Article  PubMed  CAS  Google Scholar 

  55. Gustafsson MK, Pan H, Pinney DF, Liu Y, Lewandowski A, Epstein DJ, Emerson CP Jr (2002) Myf5 is a direct target of long-range Shh signaling and Gli regulation for muscle specification. Genes Dev 16(1):114–126

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Jacob J, Briscoe J (2003) Gli proteins and the control of spinal-cord patterning. EMBO Rep 4(8):761–765

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  57. Vokes SA, Ji H, McCuine S, Tenzen T, Giles S, Zhong S, Longabaugh WJ, Davidson EH, Wong WH, McMahon AP (2007) Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development 134(10):1977–1989

    Article  PubMed  CAS  Google Scholar 

  58. Zhang XM, Lin E, Yang XJ (2000) Sonic hedgehog-mediated ventralization disrupts formation of the midbrain–hindbrain junction in the chick embryo. Dev Neurosci 22(3):207–216

    Article  PubMed  CAS  Google Scholar 

  59. Hallonet ME, Teillet MA, Le Douarin NM (1990) A new approach to the development of the cerebellum provided by the quail-chick marker system. Development 108:19–31

    PubMed  CAS  Google Scholar 

  60. Hallonet ME, Le Douarin NM (1993) Tracing neuroepithelial cells of the mesencephalic and metencephalic alar plates during cerebellar ontogeny in quail-chick chimaeras. Eur J Neurosci 5(9):1145–1155

    Article  PubMed  CAS  Google Scholar 

  61. Hallonet ME, Alvarado-Mallart RM (1997) The chick/quail chimeric system: a model for early cerebellar development. Perspect Dev Neurobiol 5(1):17–31

    PubMed  CAS  Google Scholar 

  62. Broccoli V, Boncinelli E, Wurst W (1999) The caudal limit of Otx2 expression positions the isthmic organizer. Nature 401(6749):164–168

    Article  PubMed  CAS  Google Scholar 

  63. Li JY, Lao Z, Joyner AL (2005) New regulatory interactions and cellular responses in the isthmic organizer region revealed by altering Gbx2 expression. Development 132(8):1971–1981

    Article  PubMed  CAS  Google Scholar 

  64. Martinez S, Wassef M, Alvarado-Mallart RM (1991) Induction of a mesencephalic phenotype in the 2-day-old chick prosencephalon is preceded by the early expression of the homeobox gene engrailed. Neuron 6:971–981

    Article  PubMed  CAS  Google Scholar 

  65. Martinez S, Crossley PH, Cobos I, Rubenstein JL, Martin GR (1999) FGF8 induces formation of an ectopic isthmic organizer and isthmocerebellar development via a repressive effect on Otx2 expression. Development 126(6):1189–1200

    PubMed  CAS  Google Scholar 

  66. Sotelo C (2004) Cellular and genetic regulation of the development of the cerebellar system. Prog Neurobiol 72:295–339

    Article  PubMed  CAS  Google Scholar 

  67. Leto K, Arancillo M, Becker EBE, Buffo A, Chiang C, Ding B, Dobyns WB, Dusart I, Haldipur P, Hatten ME, et al (2015) Consensus paper: cerebellar development. Cerebellum. doi:10.1007/s12311-015-0724-2

    Google Scholar 

  68. Epstein DJ, McMahon AP, Joyner AL (1999) Regionalization of sonic hedgehog transcription along the anteroposterior axis of the mouse central nervous system is regulated by Hnf3-dependent and -independent mechanisms. Development 126(2):281–292

    PubMed  CAS  Google Scholar 

  69. Kim JJ, Gill PS, Rotin L, van Eede M, Henkelman RM, Hui CC, Rosenblum ND (2011) Suppressor of fused controls mid–hindbrain patterning and cerebellar morphogenesis via GLI3 repressor. J Neurosci 31(5):1825–1836

    Article  PubMed  CAS  Google Scholar 

  70. Altman J, Bayer SA (1997) Development of the cerebellar system: in relation to its evolution, structure, and functions. CRC Press, New York

    Google Scholar 

  71. Huang X, Liu J, Ketova T, Fleming JT, Grover VK, Cooper MK, Litingtung Y, Chiang C (2010) Transventricular delivery of sonic hedgehog is essential to cerebellar ventricular zone development. Proc Natl Acad Sci USA 107:8422–8427

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  72. Dahmane N, Ruiz i Altaba A (1999) Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126:3089–3100

    PubMed  Google Scholar 

  73. Corrales JD, Rocco GL, Blaess S, Guo Q, Joyner AL (2004) Spatial pattern of sonic hedgehog signaling through Gli genes during cerebellum development. Development 131:5581–5590

    Article  PubMed  CAS  Google Scholar 

  74. Lewis PM, Gritli-Linde A, Smeyne R, Kottmann A, McMahon AP (2004) Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum. Dev Biol 270:393–410

    Article  PubMed  CAS  Google Scholar 

  75. Hoshino M, Nakamura S, Mori K, Kawauchi T, Terao M, Nishimura YV, Fukuda A, Fuse T, Matsuo N, Sone M et al (2005) Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron 47:201–213

    Article  PubMed  CAS  Google Scholar 

  76. Akazawa C, Ishibashi M, Shimizu C, Nakanishi S, Kageyama R (1995) A mammalian helix-loop-helix factor structurally related to the product of Drosophila proneural gene atonal is a positive transcriptional regulator expressed in the developing nervous system. J Biol Chem 270:8730–8738

    Article  PubMed  CAS  Google Scholar 

  77. Seto Y, Nakatani T, Masuyama N, Taya S, Kumai M, Minaki Y, Hamaguchi A, Inoue YU, Inoue T, Miyashita S et al (2014) Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum. Nat Commun 5:3337

    Article  PubMed  CAS  Google Scholar 

  78. Yamada M, Seto Y, Taya S, Owa T, Inoue YU, Inoue T, Kawaguchi Y, Nabeshima Y, Hoshino M (2014) Specification of spatial identities of cerebellar neuronal progenitors by Ptf1a and Atoh1 for proper production of GABAergic and glutamatergic neurons. J Neurosci 34:4786–4800

    Article  PubMed  CAS  Google Scholar 

  79. Alder J, Cho NK, Hatten ME (1996) Embryonic precursor cells from the rhombic lip are specified to a cerebellar granule neuron identity. Neuron 17:389–399

    Article  PubMed  CAS  Google Scholar 

  80. Wingate RJT (2001) The rhombic lip and early cerebellar development. Curr Opin Neurobiol 11:82–88

    Article  PubMed  CAS  Google Scholar 

  81. Machold R, Fishell G (2005) Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron 48:17–24

    Article  PubMed  CAS  Google Scholar 

  82. Wang VY, Rose MF, Zoghbi H (2005) Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron 48:31–43

    Article  PubMed  CAS  Google Scholar 

  83. Fink AJ, Englund C, Daza RA, Pham D, Lau C, Nivison M, Kowalczyk T, Hevner RF (2006) Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip. J Neurosci 26:3066–3076

    Article  PubMed  CAS  Google Scholar 

  84. Englund C, Kowalczyk T, Daza RA, Dagan A, Lau C, Rose MF, Hevner RF (2006) Unipolar brush cells of the cerebellum are produced in the rhombic lip and migrate through developing white matter. J Neurosci 26:9184–9195

    Article  PubMed  CAS  Google Scholar 

  85. Carletti B, Rossi F (2008) Neurogenesis in the cerebellum. The Neuroscientist 14:91–100

    Article  PubMed  Google Scholar 

  86. Fleming JT, He W, Hao C, Ketova T, Pan FC, Wright CV, Litingtung Y, Chiang C (2013) The Purkinje neuron acts as a central regulator of spatially and functionally distinct cerebellar precursors. Dev Cell 27:278–292

    Article  PubMed  CAS  Google Scholar 

  87. Miale IL, Sidman RL (1961) An autoradiographic analysis of histogenesis in the mouse cerebellum. Exp Neurol 4:277–296

    Article  PubMed  CAS  Google Scholar 

  88. Fujita S, Simada M, Nakanuna T (1966) 3H-thymidine autoradiographic studies on the cell proliferation and differentiation in the external and internal granular layers of the mouse cerebellum. J Comp Neurol 128:191–209

    Article  PubMed  CAS  Google Scholar 

  89. Sidman RL, Lane PW, Dickie MM (1962) Staggerer, a new mutation in the mouse affecting the cerebellum. Science 137(3530):610–612

    Article  PubMed  CAS  Google Scholar 

  90. Rakic P, Sidman RL (1973) Organization of cerebellar cortex secondary to deficit of granule cells in weaver mutant mice. J Comp Neurol 152(2):133–161

    Article  PubMed  CAS  Google Scholar 

  91. Herrup K, Mullen RJ (1979) Staggerer chimeras: intrinsic nature of Purkinje cell defects and implications for normal cerebellar development. Brain Res 178(2–3):443–457

    Article  PubMed  CAS  Google Scholar 

  92. Doughty ML, Delhaye-Bouchaud N, Mariani J (1998) Quantitative analysis of cerebellar lobulation in normal and agranular rats. J Comp Neurol 399:306–320

    Article  PubMed  CAS  Google Scholar 

  93. Corrales JD, Blaess S, Mahoney EM, Joyner AL (2006) The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation. Development 133:1811–1821

    Article  PubMed  CAS  Google Scholar 

  94. Behesti H, Marino S (2009) Cerebellar granule cells: insights into proliferation, differentiation, and role in medulloblastoma pathogenesis. Int J Biochem Cell Biol 41(3):435–445

    Article  PubMed  CAS  Google Scholar 

  95. Roussel MF, Hatten ME (2011) Cerebellum development and medulloblastoma. Curr Top Dev Biol 94:235–282

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  96. Choi Y, Borghesani PR, Chan JA, Segal RA (2005) Migration from a mitogenic niche promotes cell-cycle exit. J Neurosci 25(45):10437–10445

    Article  PubMed  CAS  Google Scholar 

  97. Ishizaki Y (2006) Control of proliferation and differentiation of neural precursor cells: focusing on the developing cerebellum. J Pharmacol Sci 101(3):183–188

    Article  PubMed  CAS  Google Scholar 

  98. Sonmez E, Herrup K (1984) Role of staggerer gene in determining cell number in cerebellar cortex. II. Granule cell death and persistence of the external granule cell layer in young mouse chimeras. Brain Res 314(2):271–283

    Article  PubMed  CAS  Google Scholar 

  99. Vogel MW, Sunter K, Herrup K (1989) Numerical matching between granule and Purkinje cells in lurcher chimeric mice: a hypothesis for the trophic rescue of granule cells from target-related cell death. J Neurosci 9(10):3454–3462

    PubMed  CAS  Google Scholar 

  100. Smeyne RJ, Chu T, Lewin A, Bian F, S.-Crisman S, Kunsch C, Lira SA, Oberdick J (1995) Local control of granule cell generation by cerebellar Purkinje cells. Mol Cell Neurosci 6:230–251

    Article  PubMed  CAS  Google Scholar 

  101. Mullen RJ, Eicher EM, Sidman RL (1976) Purkinje cell degeneration, a new neurological mutation in the mouse. Proc Natl Acad Sci USA 73(1):208–212

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  102. Wallace VA (1999) Purkinje-cell-derived sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol 9:445–448

    Article  PubMed  CAS  Google Scholar 

  103. Wechsler-Reya RJ, Scott MP (1999) Control of neuronal precursor proliferation in the cerebellum by sonic hedgehog. Neuron 22:103–114

    Article  PubMed  CAS  Google Scholar 

  104. Nicot A, Lelièvre V, Tam J, Waschek JA, DiCicco-Bloom E (2002) Pituitary adenylate cyclase-activating polypeptide and sonic hedgehog interact to control cerebellar granule precursor cell proliferation. J Neurosci 22(21):9244–9254

    PubMed  CAS  Google Scholar 

  105. Knoepfler PS, Cheng PF, Eisenman RN (2002) N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev 16(20):2699–2712

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  106. Kenney AM, Cole MD, Rowitch DH (2003) Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130:15–28

    Article  PubMed  CAS  Google Scholar 

  107. Shambaugh GE 3rd, Lee RJ, Watanabe G, Erfurth F, Karnezis AN, Koch AE, Haines GK 3rd, Halloran M, Brody BA, Pestell RG (1996) Reduced cyclin D1 expression in the cerebella of nutritionally deprived rats correlates with developmental delay and decreased cellular DNA synthesis. J Neuropathol Exp Neurol 55(9):1009–1020

    Article  PubMed  CAS  Google Scholar 

  108. Watanabe G, Pena P, Shambaugh GE 3rd, Haines GK 3rd, Pestell RG (1998) Regulation of cyclin dependent kinase inhibitor proteins during neonatal cerebella development. Brain Res Dev Brain Res 108(1–2):77–87

    Article  PubMed  CAS  Google Scholar 

  109. Parmigiani E, Leto K, Rolando C, Figueres-Onãte M, López-Mascaraque L, Buffo A, Rossi F (2015) Heterogeneity and bipotency of astroglial-like cerebellar progenitors along the interneuron and glial lineages. J Neurosci 35(19):7388–7402

    Article  PubMed  CAS  Google Scholar 

  110. Durand B, Fero ML, Roberts JM, Raff MC (1998) p27Kip1 alters the response of cells to mitogen and is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation. Curr Biol 8(8):431–440

    Article  PubMed  CAS  Google Scholar 

  111. Miyazawa K, Himi T, Garcia V, Yamagishi H, Sato S, Ishizaki Y (2000) A role for p27/Kip1 in the control of cerebellar granule cell precursor proliferation. J Neurosci 20(15):5756–5763

    PubMed  CAS  Google Scholar 

  112. Pons S, Trejo JL, Martinez-Morales JR, Marti E (2001) Vitronectin regulates Sonic hedgehog activity during cerebellum development through CREB phosphorylation. Development 128(9):1481–1492

    PubMed  CAS  Google Scholar 

  113. Weisheit G, Gliem M, Endl E, Pfeffer PL, Busslinger M, Schilling K (2006) Postnatal development of the murine cerebellar cortex: formation and early dispersal of basket, stellate and Golgi neurons. Eur J Neurosci 24:466–478

    Article  PubMed  Google Scholar 

  114. Maricich SM, Herrup K (1999) Pax-2 expression defines a subset of GABAergic interneurons and their precursors in the developing murine cerebellum. J Neurobiol 41:281–294

    Article  PubMed  CAS  Google Scholar 

  115. Zhang L, Goldman JE (1996) Generation of cerebellar interneurons from dividing progenitors in white matter. Neuron 16(1):47–54

    Article  PubMed  Google Scholar 

  116. Leto K, Carletti B, Williams IM, Magrassi L, Rossi F (2006) Different types of cerebellar GABAergic interneurons originate from a common pool of multipotent progenitor cells. J Neurosci 26:11682–11694

    Article  PubMed  CAS  Google Scholar 

  117. Leto K, Bartolini A, Yanagawa Y, Obata K, Magrassi L, Schilling K, Rossi F (2009) Laminar fate and phenotype specification of cerebellar GABAergic interneurons. J Neurosci 29:7079–7091

    Article  PubMed  CAS  Google Scholar 

  118. Sudarov A, Turnbull RK, Kim EJ, Lebel-Potter M, Guillemot F, Joyner AL (2011) Ascl1 genetics reveals insights into cerebellum local circuit assembly. J Neurosci 31:11055–11069

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  119. De Luca A, Parmigiani E, Tosatto G, Martire S, Hoshino M, Buffo A, Leto K, Rossi F (2015) Exogenous sonic hedgehog modulates the pool of GABAergic interneurons during cerebellar development. Cerebellum. 14:72–85

    Article  PubMed  CAS  Google Scholar 

  120. Schilling K, Oberdick J, Rossi F, Baader SL (2008) Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex. Histochem Cell Biol 130:601–615

    Article  PubMed  CAS  Google Scholar 

  121. Ramón y Cajal S (1911) Histologie du système nerveux de l’homme et des vertébrés. Maloine, Paris

    Google Scholar 

  122. Palay SL, Chan-Palay V (1974) Cerebellar cortex. Springer, Berlin

    Book  Google Scholar 

  123. Buffo A, Rossi F (2013) Origin, lineage and function of cerebellar glia. Prog Neurobiol 109:42–63

    Article  PubMed  Google Scholar 

  124. Yuasa S (1996) Bergmann glial development in the mouse cerebellum as revealed by tenascin expression. Anat Embryol 194:223–234

    Article  PubMed  CAS  Google Scholar 

  125. Yamada K, Watanabe M (2002) Cytodifferentiation of Bergmann glia and its relationship with Purkinje cells. Anat Sci Int 77:94–108

    Article  PubMed  Google Scholar 

  126. Mori T, Tanaka K, Buffo A, Wurst W, Kuehn R, Goetz M (2006) Inducible gene deletion in astroglia and radial glia—a valuable tool for functional and lineage analysis. Glia. 54:21–34

    Article  PubMed  Google Scholar 

  127. Sotelo C, Alvarado-Mallart RM (1991) The reconstruction of cerebellar circuits. Trends Neurosci 14(8):350–355

    Article  PubMed  CAS  Google Scholar 

  128. Rossi F, Borsello T, Strata P (1992) Embryonic Purkinje cells grafted on the surface of the cerebellar cortex integrate in the adult unlesioned cerebellum. Eur J Neurosci 4(6):589–593

    Article  PubMed  Google Scholar 

  129. Grimaldi P, Parras C, Guillemot F, Rossi F, Wassef M (2009) Origins and control of the differentiation of inhibitory interneurons and glia in the cerebellum. Dev Biol 328:422–433

    Article  PubMed  CAS  Google Scholar 

  130. Wallace VA, Raff MC (1999) A role for sonic hedgehog in axon-to-astrocyte signalling in the rodent optic nerve. Development 126(13):2901–2909

    PubMed  CAS  Google Scholar 

  131. Sehgal R, Sheibani N, Rhodes SJ, Belecky Adams TL (2009) BMP7 and SHH regulate Pax2 in mouse retinal astrocytes by relieving TLX repression. Dev Biol 332(2):429–443

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  132. Garcia AD, Petrova R, Eng L, Joyner AL (2010) Sonic hedgehog regulates discrete populations of astrocytes in the adult mouse forebrain. J Neurosci 30(41):13597–13608

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  133. Poncet C, Soula C, Trousse F, Kan P, Hirsinger E, Pourquié O, Duprat AM, Cochard A (1996) Induction of oligodendrocyte progenitors in the trunk neural tube by ventralizing signals: effects of notochord and floor plate grafts, and of sonic hedgehog. Mech Dev 60(1):13–32

    Article  PubMed  CAS  Google Scholar 

  134. Lu QR, Yuk D, Alberta JA, Zhu Z, Pawlitzky I, Chan J, McMahon AP, Stiles CD, Rowitch DH (2000) Sonic hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 25:317–329

    Article  PubMed  CAS  Google Scholar 

  135. Lu Q, Sun T, Zhu Z, Ma N, Garcia M, Stiles CD, Rowitch DH (2002) Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109:75–86

    Article  PubMed  CAS  Google Scholar 

  136. Alberta JA, Park SK, Mora J, Yuk D, Pawlitzky I, Iannarelli P, Vartanian T, Stiles CD, Rowitch DH (2001) Sonic hedgehog is required during an early phase of oligodendrocyte development in mammalian brain. Mol Cell Neurosci 18(4):434–441

    Article  PubMed  CAS  Google Scholar 

  137. Merchán P, Bribián A, Sánchez-Camacho C, Lezameta M, Bovolenta P, de Castro F (2007) Sonic hedgehog promotes the migration and proliferation of optic nerve oligodendrocyte precursors. Mol Cell Neurosci 36(3):355–368

    Article  PubMed  CAS  Google Scholar 

  138. Ortega MC, Cases O, Merchán P, Kozyraki R, Clemente D, de Castro F (2012) Megalin mediates the influence of sonic hedgehog on oligodendrocyte precursor cell migration and proliferation during development. Glia 60(6):851–866

    Article  PubMed  Google Scholar 

  139. Traiffort E, Charytoniuk DA, Faure H, Ruat M (1998) Regional distribution of sonic hedgehog, patched, and smoothened mRNA in the adult rat brain. J Neurochem 70(3):1327–1330

    Article  PubMed  CAS  Google Scholar 

  140. Fisher M, Trimmer P, Ruthel G (1993) Bergmann glia require continuous association with Purkinje cells for normal phenotype expression. Glia 8(3):172–182

    Article  PubMed  CAS  Google Scholar 

  141. Mecklenburg N, Martinez-Lopez JE, Moreno-Bravo JA, Perez-Balaguer A, Puelles E, Martinez S (2014) Growth and differentiation factor 10 (Gdf10) is involved in Bergmann glial cell development under Shh regulation. Glia 62(10):1713–1723

    Article  PubMed  Google Scholar 

  142. Bouslama-Oueghlani L, Wehrlé R, Doulazmi M, Chen XR, Jaudon F, Lemaigre-Dubreuil Y, Rivals I, Sotelo C, Dusart I (2012) Purkinje cell maturation participates in the control of oligodendrocyte differentiation: role of sonic hedgehog and vitronectin. PLoS One 7(11):e49015

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  143. Barres BA, Raff MC (1993) Proliferation of oligodendrocyte precursor cells depends on electrical activity in axons. Nature 361(6409):258–260

    Article  PubMed  CAS  Google Scholar 

  144. Burne JF, Staple JK, Raff MC (1996) Glial cells are increased proportionally in transgenic optic nerves with increased numbers of axons. J Neurosci 16(6):2064–2073

    PubMed  CAS  Google Scholar 

  145. Trapp BD, Nishiyama A, Cheng D, Macklin W (1997) Differentiation and death of premyelinating oligodendrocytes in developing rodent brain. J Cell Biol 137(2):459–468

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  146. Sudarov A, Joyner AL (2007) Cerebellum morphogenesis: the foliation pattern is orchestrated by multi-cellular anchoring centers. Neural Dev 3:26

    Article  CAS  Google Scholar 

  147. Kool M, Koster J, Bunt J, Hasselt NE, Lakeman A, van Sluis P, Troost D, Meeteren NS, Caron HN, Cloos J et al (2008) Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 3:e3088

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, Bouffet E, Clifford SC, Hawkins CE, French P et al (2011) Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29:1408–1414

    Article  PubMed  Google Scholar 

  149. Northcott PA, Hielscher T, Dubuc A, Mack S, Shih D, Remke M, Al-Halabi H, Albrecht S, Jabado N, Eberhart CG et al (2011) Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropath 122:231–240

    Article  PubMed  PubMed Central  Google Scholar 

  150. Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stütz AM, Korshunov A, Reimand J, Schumacher SE et al (2012) Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488:49–56

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  151. Aref D, Moffatt CJ, Agnihotri S, Ramaswamy V, Dubuc AM, Northcott PA, Taylor MD, Perry A, Olson JM, Eberhart CG et al (2012) Canonical TGF-beta pathway activity is a predictor of SHH-driven medulloblastoma survival and delineates putative precursors in cerebellar development. Brain Pathol 23(2):178–191

    Article  PubMed  CAS  Google Scholar 

  152. Oliver TG, Read TA, Kessler JD, Mehmeti A, Wells JF, Huynh TT, Lin SM, Wechsler-Reya RJ (2005) Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma. Development 132:2425–2439

    Article  PubMed  CAS  Google Scholar 

  153. Crawford JR, MacDonald TJ, Packer RJ (2007) Medulloblastoma in childhood: new biological advances. Lancet Neurol 6:1073–1085

    Article  PubMed  CAS  Google Scholar 

  154. Raffel C (2004) Medulloblastoma: molecular genetics and animal models. Neoplasia 6:310–322

    Article  PubMed  PubMed Central  Google Scholar 

  155. Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiapa S, Gao L, Lowrance A et al (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet 31:306–310

    Article  PubMed  CAS  Google Scholar 

  156. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A et al (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123:465–472

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  157. Eberhart CG (2003) Medulloblastoma in Mice Lacking p53 and PARP. All roads lead to Gli. Am J Pathol 162(1):7–10

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  158. Hatton BA, Villavicencio EH, Tsuchiya KD, Pritchard JI, Ditzler S, Pullar B, Hansen S, Knoblaugh SE, Lee D, Eberhart CG et al (2008) The Smo/Smo model: hedgehog-induced medulloblastoma with 90 % incidence and leptomeningeal spread. Cancer Res 68(6):1768–1776

    Article  PubMed  CAS  Google Scholar 

  159. Goodrich LV, Milenkovic L, Higgins KM, Scott MP (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277:1109–1113

    Article  PubMed  CAS  Google Scholar 

  160. Goodrich LV, Scott MP (1998) Hedgehog and patched in neural development and disease. Neuron 21:1243–1257

    Article  PubMed  CAS  Google Scholar 

  161. Gorlin RJ (1995) Nevoid basal cell carcinoma syndrome. Dermatol Clin 13:113–125

    PubMed  CAS  Google Scholar 

  162. Kim J, Nelson AL, Algon SA, Graves O, Sturla LM, Goumnerova LC, Rowitch DH, Segal RA, Pomeroy SL (2003) Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice. Dev Biol 263:50–66

    Article  PubMed  CAS  Google Scholar 

  163. Brugières L, Remenieras A, Pierron G, Varlet P, Forget S, Byrde V, Bombled J, Puget S, Caron O, Dufour C et al (2012) High frequency of germline SUFU mutations in children with desmoplastic/nodular medulloblastoma younger than 3 years of age. J Clin Oncol 30:2087–2093

    Article  PubMed  CAS  Google Scholar 

  164. Smith MJ, Beetz C, Williams SG, Bhaskar SS, O’Sullivan J, Anderson B, Daly SB, Urquhart JE, Bholah Z, Oudit D et al (2014) Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol 32(36):4155–4161

    Article  PubMed  CAS  Google Scholar 

  165. Yoon JW, Gilbertson R, Iannaccone S, Iannaccone P, Walterhouse D (2008) Defining a role for sonic hedgehog pathway activation in desmoplastic medulloblastoma by identifying GLI1 target genes. Int J Cancer 124:109–119

    Article  CAS  Google Scholar 

  166. Buczkowicz P, Ma J, Hawkins C (2011) GLI2 is a potential therapeutic target in pediatric medulloblastoma. J Neuropathol Exp Neurol 70(6):430–437

    Article  PubMed  CAS  Google Scholar 

  167. Li P, Du F, Yuelling LW, Lin T, Muradimova RE, Tricarico R, Wang J, Enikolopov G, Bellacosa A, Whechsler-Reya RJ et al (2013) A population of Nestin-expressing progenitors in the cerebellum exhibits increased tumorigenicity. Nat Neurosci 16(12):1737–1744

    Article  PubMed  CAS  Google Scholar 

  168. Park M, Park HJ, Eom HS, Kwon YJ, Park JA, Lim YJ, Yoon JH, Kong SY, Ghim TT, Lee HW et al (2013) Safety and effects of prophylactic defibrotide for sinusoidal obstruction syndrome in hematopoietic stem cell transplantation. Ann Transplant 18:36–42

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We dedicate this work to the memory of Prof. F. Rossi for his continuous support and encouragement. This work was supported by the University of Turin and Research Fund for the Promotion of Basic Research Grant RBFR10A01S (K.L.). We thank Professor Richard Hawkes, Dr. Daniela Carulli, and Dr. Ishira Nanavaty for critical reading of this manuscript and helpful suggestions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ketty Leto.

Ethics declarations

Conflict of interest

The author(s) declare that they have no competing interests.

Additional information

Annarita De Luca and Valentina Cerrato contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

De Luca, A., Cerrato, V., Fucà, E. et al. Sonic hedgehog patterning during cerebellar development. Cell. Mol. Life Sci. 73, 291–303 (2016). https://doi.org/10.1007/s00018-015-2065-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-015-2065-1

Keywords

Navigation