Cellular and Molecular Life Sciences

, Volume 73, Issue 2, pp 291–303 | Cite as

Sonic hedgehog patterning during cerebellar development

  • Annarita De Luca
  • Valentina Cerrato
  • Elisa Fucà
  • Elena Parmigiani
  • Annalisa Buffo
  • Ketty Leto


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.


Shh Mitogen Differentiation Cerebellum 


  1. 1.
    Simpson F, Kerr MC, Wicking C (2009) Trafficking, development and hedgehog. Mech Dev 126(5–6):279–288PubMedCrossRefGoogle Scholar
  2. 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):183–189PubMedCrossRefGoogle Scholar
  3. 3.
    Nüsslein-Volhard C, Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287(5785):795–801PubMedCrossRefGoogle Scholar
  4. 4.
    Martinez-Arias A, Lawrence PA (1985) Parasegments and compartments in the Drosophila embryo. Nature 313(6004):639–642PubMedCrossRefGoogle Scholar
  5. 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):133–141PubMedPubMedCentralCrossRefGoogle Scholar
  6. 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):3339–3353PubMedGoogle Scholar
  7. 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):1417–1430PubMedCrossRefGoogle Scholar
  8. 8.
    Machold R, Fishell G (2002) Hedgehog patterns midbrain architecture. Trends Neurosci 25(1):10–11PubMedCrossRefGoogle Scholar
  9. 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):772–783PubMedCrossRefGoogle Scholar
  10. 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):965–973PubMedCrossRefGoogle Scholar
  11. 11.
    Vaillant C, Monard D (2009) SHH pathway and cerebellar development. Cerebellum 8(3):291–301PubMedCrossRefGoogle Scholar
  12. 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):801–814PubMedCrossRefGoogle Scholar
  13. 13.
    Bale AE (2002) Hedgehog signaling and human disease. Annu Rev Genomics Hum Genet 3:47–65PubMedCrossRefGoogle Scholar
  14. 14.
    Teglund S, Toftgard R (1805) Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta 2:181–208Google Scholar
  15. 15.
    Varjosalo M, Taipale J (2008) Hedgehog: functions and mechanisms. Genes Dev 22(18):2454–2472PubMedCrossRefGoogle Scholar
  16. 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):16951–16956PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Millen KL, Gleeson JG (2008) Cerebellar development and disease. Curr Opin Neurobiol 18(1):12–19PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Barakat MT, Humke EW, Scott MP (2013) Kif3a is necessary for initiation and maintenance of medulloblastoma. Carcinogenesis 34(6):1382–1392PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Porter JA, Young KE, Beachy PA (1996) Cholesterol modification of hedgehog signaling proteins in animal development. Science 274(5285):255–259PubMedCrossRefGoogle Scholar
  20. 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):439–440Google Scholar
  21. 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):2080–2084PubMedCrossRefGoogle Scholar
  22. 22.
    Lee JJ, Ekker SC, von Kessler DP, Porter JA, Sun BI, Beachy PA (1994) Autoproteolysis in hedgehog protein biogenesis. Science 266(5190):1528–1537PubMedCrossRefGoogle Scholar
  23. 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):14037–14045PubMedCrossRefGoogle Scholar
  24. 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):599–612PubMedCrossRefGoogle Scholar
  25. 25.
    Wang Y, McMahon AP, Allen BL (2007) Shifting paradigms in Hedgehog signaling. Curr Opin Cell Biol 19(2):159–165PubMedCrossRefGoogle Scholar
  26. 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):716–720PubMedCrossRefGoogle Scholar
  27. 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):641–659PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Fico A, Maina F, Dono R (2011) Fine-tuning of cell signaling by glypicans. Cell Mol Life Sci 68(6):923–929PubMedCrossRefGoogle Scholar
  29. 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):364–386PubMedCrossRefGoogle Scholar
  30. 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):25660–25667PubMedCrossRefGoogle Scholar
  31. 31.
    Litingtung Y, Chiang C (2000) Control of Shh activity and signaling in the neural tube. Dev Dyn 219(2):143–154PubMedCrossRefGoogle Scholar
  32. 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):788–801PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Marigo V, Davey RA, Zuo Y, Cunningham JM, Tabin CJ (1996) Biochemical evidence that patched is the hedgehog receptor. Nature 384(6605):176–179PubMedCrossRefGoogle Scholar
  34. 34.
    Kang JS, Zhang W, Krauss RS (2007) Hedgehog signaling: cooking with Gas1. Sci STKE 403:pe50Google Scholar
  35. 35.
    Taipale J, Cooper MK, Maiti T, Beachy PA (2002) Patched acts catalytically to suppress the activity of Smoothened. Nature 418(6900):892–897PubMedCrossRefGoogle Scholar
  36. 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):e1001083PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Cohen MM Jr (2010) Hedgehog signaling update. Am J Med Genet A 152A(8):1875–1914PubMedCrossRefGoogle Scholar
  38. 38.
    Goetz SC, Anderson KV (2010) The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11(5):331–344PubMedPubMedCentralCrossRefGoogle Scholar
  39. 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):246–259PubMedPubMedCentralCrossRefGoogle Scholar
  40. 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):9780–9789PubMedCrossRefGoogle Scholar
  41. 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):8627–8641PubMedPubMedCentralCrossRefGoogle Scholar
  42. 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):187–197PubMedCrossRefGoogle Scholar
  43. 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):7042–7053PubMedPubMedCentralCrossRefGoogle Scholar
  44. 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):7054–7068PubMedPubMedCentralCrossRefGoogle Scholar
  45. 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):423–434PubMedCrossRefGoogle Scholar
  46. 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):3365–3377PubMedPubMedCentralCrossRefGoogle Scholar
  47. 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):719–729PubMedCrossRefGoogle Scholar
  48. 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):10846–10852PubMedCrossRefGoogle Scholar
  49. 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):359–370PubMedPubMedCentralCrossRefGoogle Scholar
  50. 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):2222–2230PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15(23):3059–3087PubMedCrossRefGoogle Scholar
  52. 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):415–428PubMedPubMedCentralCrossRefGoogle Scholar
  53. 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):7331–7336PubMedPubMedCentralCrossRefGoogle Scholar
  54. 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):903–915PubMedCrossRefGoogle Scholar
  55. 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):114–126PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Jacob J, Briscoe J (2003) Gli proteins and the control of spinal-cord patterning. EMBO Rep 4(8):761–765PubMedPubMedCentralCrossRefGoogle Scholar
  57. 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):1977–1989PubMedCrossRefGoogle Scholar
  58. 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):207–216PubMedCrossRefGoogle Scholar
  59. 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 108:19–31PubMedGoogle Scholar
  60. 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):1145–1155PubMedCrossRefGoogle Scholar
  61. 61.
    Hallonet ME, Alvarado-Mallart RM (1997) The chick/quail chimeric system: a model for early cerebellar development. Perspect Dev Neurobiol 5(1):17–31PubMedGoogle Scholar
  62. 62.
    Broccoli V, Boncinelli E, Wurst W (1999) The caudal limit of Otx2 expression positions the isthmic organizer. Nature 401(6749):164–168PubMedCrossRefGoogle Scholar
  63. 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):1971–1981PubMedCrossRefGoogle Scholar
  64. 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 6:971–981PubMedCrossRefGoogle Scholar
  65. 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):1189–1200PubMedGoogle Scholar
  66. 66.
    Sotelo C (2004) Cellular and genetic regulation of the development of the cerebellar system. Prog Neurobiol 72:295–339PubMedCrossRefGoogle Scholar
  67. 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. 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):281–292PubMedGoogle Scholar
  69. 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):1825–1836PubMedCrossRefGoogle Scholar
  70. 70.
    Altman J, Bayer SA (1997) Development of the cerebellar system: in relation to its evolution, structure, and functions. CRC Press, New YorkGoogle Scholar
  71. 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 107:8422–8427PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Dahmane N, Ruiz i Altaba A (1999) Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126:3089–3100PubMedGoogle Scholar
  73. 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 131:5581–5590PubMedCrossRefGoogle Scholar
  74. 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 270:393–410PubMedCrossRefGoogle Scholar
  75. 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 47:201–213PubMedCrossRefGoogle Scholar
  76. 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 270:8730–8738PubMedCrossRefGoogle Scholar
  77. 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 5:3337PubMedCrossRefGoogle Scholar
  78. 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 34:4786–4800PubMedCrossRefGoogle Scholar
  79. 79.
    Alder J, Cho NK, Hatten ME (1996) Embryonic precursor cells from the rhombic lip are specified to a cerebellar granule neuron identity. Neuron 17:389–399PubMedCrossRefGoogle Scholar
  80. 80.
    Wingate RJT (2001) The rhombic lip and early cerebellar development. Curr Opin Neurobiol 11:82–88PubMedCrossRefGoogle Scholar
  81. 81.
    Machold R, Fishell G (2005) Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron 48:17–24PubMedCrossRefGoogle Scholar
  82. 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 48:31–43PubMedCrossRefGoogle Scholar
  83. 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 26:3066–3076PubMedCrossRefGoogle Scholar
  84. 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 26:9184–9195PubMedCrossRefGoogle Scholar
  85. 85.
    Carletti B, Rossi F (2008) Neurogenesis in the cerebellum. The Neuroscientist 14:91–100PubMedCrossRefGoogle Scholar
  86. 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 27:278–292PubMedCrossRefGoogle Scholar
  87. 87.
    Miale IL, Sidman RL (1961) An autoradiographic analysis of histogenesis in the mouse cerebellum. Exp Neurol 4:277–296PubMedCrossRefGoogle Scholar
  88. 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 128:191–209PubMedCrossRefGoogle Scholar
  89. 89.
    Sidman RL, Lane PW, Dickie MM (1962) Staggerer, a new mutation in the mouse affecting the cerebellum. Science 137(3530):610–612PubMedCrossRefGoogle Scholar
  90. 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):133–161PubMedCrossRefGoogle Scholar
  91. 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):443–457PubMedCrossRefGoogle Scholar
  92. 92.
    Doughty ML, Delhaye-Bouchaud N, Mariani J (1998) Quantitative analysis of cerebellar lobulation in normal and agranular rats. J Comp Neurol 399:306–320PubMedCrossRefGoogle Scholar
  93. 93.
    Corrales JD, Blaess S, Mahoney EM, Joyner AL (2006) The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation. Development 133:1811–1821PubMedCrossRefGoogle Scholar
  94. 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):435–445PubMedCrossRefGoogle Scholar
  95. 95.
    Roussel MF, Hatten ME (2011) Cerebellum development and medulloblastoma. Curr Top Dev Biol 94:235–282PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Choi Y, Borghesani PR, Chan JA, Segal RA (2005) Migration from a mitogenic niche promotes cell-cycle exit. J Neurosci 25(45):10437–10445PubMedCrossRefGoogle Scholar
  97. 97.
    Ishizaki Y (2006) Control of proliferation and differentiation of neural precursor cells: focusing on the developing cerebellum. J Pharmacol Sci 101(3):183–188PubMedCrossRefGoogle Scholar
  98. 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):271–283PubMedCrossRefGoogle Scholar
  99. 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):3454–3462PubMedGoogle Scholar
  100. 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 6:230–251PubMedCrossRefGoogle Scholar
  101. 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):208–212PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Wallace VA (1999) Purkinje-cell-derived sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol 9:445–448PubMedCrossRefGoogle Scholar
  103. 103.
    Wechsler-Reya RJ, Scott MP (1999) Control of neuronal precursor proliferation in the cerebellum by sonic hedgehog. Neuron 22:103–114PubMedCrossRefGoogle Scholar
  104. 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):9244–9254PubMedGoogle Scholar
  105. 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):2699–2712PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Kenney AM, Cole MD, Rowitch DH (2003) Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130:15–28PubMedCrossRefGoogle Scholar
  107. 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):1009–1020PubMedCrossRefGoogle Scholar
  108. 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):77–87PubMedCrossRefGoogle Scholar
  109. 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):7388–7402PubMedCrossRefGoogle Scholar
  110. 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):431–440PubMedCrossRefGoogle Scholar
  111. 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):5756–5763PubMedGoogle Scholar
  112. 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):1481–1492PubMedGoogle Scholar
  113. 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 24:466–478PubMedCrossRefGoogle Scholar
  114. 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 41:281–294PubMedCrossRefGoogle Scholar
  115. 115.
    Zhang L, Goldman JE (1996) Generation of cerebellar interneurons from dividing progenitors in white matter. Neuron 16(1):47–54PubMedCrossRefGoogle Scholar
  116. 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 26:11682–11694PubMedCrossRefGoogle Scholar
  117. 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 29:7079–7091PubMedCrossRefGoogle Scholar
  118. 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 31:11055–11069PubMedPubMedCentralCrossRefGoogle Scholar
  119. 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. 14:72–85PubMedCrossRefGoogle Scholar
  120. 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 130:601–615PubMedCrossRefGoogle Scholar
  121. 121.
    Ramón y Cajal S (1911) Histologie du système nerveux de l’homme et des vertébrés. Maloine, ParisGoogle Scholar
  122. 122.
    Palay SL, Chan-Palay V (1974) Cerebellar cortex. Springer, BerlinCrossRefGoogle Scholar
  123. 123.
    Buffo A, Rossi F (2013) Origin, lineage and function of cerebellar glia. Prog Neurobiol 109:42–63PubMedCrossRefGoogle Scholar
  124. 124.
    Yuasa S (1996) Bergmann glial development in the mouse cerebellum as revealed by tenascin expression. Anat Embryol 194:223–234PubMedCrossRefGoogle Scholar
  125. 125.
    Yamada K, Watanabe M (2002) Cytodifferentiation of Bergmann glia and its relationship with Purkinje cells. Anat Sci Int 77:94–108PubMedCrossRefGoogle Scholar
  126. 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. 54:21–34PubMedCrossRefGoogle Scholar
  127. 127.
    Sotelo C, Alvarado-Mallart RM (1991) The reconstruction of cerebellar circuits. Trends Neurosci 14(8):350–355PubMedCrossRefGoogle Scholar
  128. 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):589–593PubMedCrossRefGoogle Scholar
  129. 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 328:422–433PubMedCrossRefGoogle Scholar
  130. 130.
    Wallace VA, Raff MC (1999) A role for sonic hedgehog in axon-to-astrocyte signalling in the rodent optic nerve. Development 126(13):2901–2909PubMedGoogle Scholar
  131. 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):429–443PubMedPubMedCentralCrossRefGoogle Scholar
  132. 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):13597–13608PubMedPubMedCentralCrossRefGoogle Scholar
  133. 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):13–32PubMedCrossRefGoogle Scholar
  134. 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 25:317–329PubMedCrossRefGoogle Scholar
  135. 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 109:75–86PubMedCrossRefGoogle Scholar
  136. 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):434–441PubMedCrossRefGoogle Scholar
  137. 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):355–368PubMedCrossRefGoogle Scholar
  138. 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):851–866PubMedCrossRefGoogle Scholar
  139. 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):1327–1330PubMedCrossRefGoogle Scholar
  140. 140.
    Fisher M, Trimmer P, Ruthel G (1993) Bergmann glia require continuous association with Purkinje cells for normal phenotype expression. Glia 8(3):172–182PubMedCrossRefGoogle Scholar
  141. 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):1713–1723PubMedCrossRefGoogle Scholar
  142. 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):e49015PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Barres BA, Raff MC (1993) Proliferation of oligodendrocyte precursor cells depends on electrical activity in axons. Nature 361(6409):258–260PubMedCrossRefGoogle Scholar
  144. 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):2064–2073PubMedGoogle Scholar
  145. 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):459–468PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Sudarov A, Joyner AL (2007) Cerebellum morphogenesis: the foliation pattern is orchestrated by multi-cellular anchoring centers. Neural Dev 3:26CrossRefGoogle Scholar
  147. 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:e3088PubMedPubMedCentralCrossRefGoogle Scholar
  148. 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 29:1408–1414PubMedCrossRefGoogle Scholar
  149. 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 122:231–240PubMedPubMedCentralCrossRefGoogle Scholar
  150. 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 488:49–56PubMedPubMedCentralCrossRefGoogle Scholar
  151. 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):178–191PubMedCrossRefGoogle Scholar
  152. 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 132:2425–2439PubMedCrossRefGoogle Scholar
  153. 153.
    Crawford JR, MacDonald TJ, Packer RJ (2007) Medulloblastoma in childhood: new biological advances. Lancet Neurol 6:1073–1085PubMedCrossRefGoogle Scholar
  154. 154.
    Raffel C (2004) Medulloblastoma: molecular genetics and animal models. Neoplasia 6:310–322PubMedPubMedCentralCrossRefGoogle Scholar
  155. 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 31:306–310PubMedCrossRefGoogle Scholar
  156. 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 123:465–472PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Eberhart CG (2003) Medulloblastoma in Mice Lacking p53 and PARP. All roads lead to Gli. Am J Pathol 162(1):7–10PubMedPubMedCentralCrossRefGoogle Scholar
  158. 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):1768–1776PubMedCrossRefGoogle Scholar
  159. 159.
    Goodrich LV, Milenkovic L, Higgins KM, Scott MP (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277:1109–1113PubMedCrossRefGoogle Scholar
  160. 160.
    Goodrich LV, Scott MP (1998) Hedgehog and patched in neural development and disease. Neuron 21:1243–1257PubMedCrossRefGoogle Scholar
  161. 161.
    Gorlin RJ (1995) Nevoid basal cell carcinoma syndrome. Dermatol Clin 13:113–125PubMedGoogle Scholar
  162. 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 263:50–66PubMedCrossRefGoogle Scholar
  163. 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 30:2087–2093PubMedCrossRefGoogle Scholar
  164. 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):4155–4161PubMedCrossRefGoogle Scholar
  165. 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 124:109–119CrossRefGoogle Scholar
  166. 166.
    Buczkowicz P, Ma J, Hawkins C (2011) GLI2 is a potential therapeutic target in pediatric medulloblastoma. J Neuropathol Exp Neurol 70(6):430–437PubMedCrossRefGoogle Scholar
  167. 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):1737–1744PubMedCrossRefGoogle Scholar
  168. 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 18:36–42PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Annarita De Luca
    • 1
    • 2
  • Valentina Cerrato
    • 1
    • 2
  • Elisa Fucà
    • 1
    • 2
  • Elena Parmigiani
    • 1
    • 2
  • Annalisa Buffo
    • 1
    • 2
  • Ketty Leto
    • 1
    • 2
  1. 1.Department of Neuroscience Rita Levi-MontalciniUniversity of TurinTurinItaly
  2. 2.Neuroscience Institute Cavalieri OttolenghiOrbassano, TurinItaly

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