Skip to main content
Log in

Can Clues from Evolution Unlock the Molecular Development of the Cerebellum?

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The cerebellum sits at the rostral end of the vertebrate hindbrain and is responsible for sensory and motor integration. Owing to its relatively simple architecture, it is one of the most powerful model systems for studying brain evolution and development. Over the last decade, the combination of molecular fate mapping techniques in the mouse and experimental studies, both in vitro and in vivo, in mouse and chick have significantly advanced our understanding of cerebellar neurogenesis in space and time. In amniotes, the most numerous cell type in the cerebellum, and indeed the brain, is the cerebellar granule neurons, and these are born from a transient secondary proliferative zone, the external granule layer (EGL), where proliferation is driven by sonic hedgehog signalling and causes cerebellar foliation. Recent studies in zebrafish and sharks have shown that while the molecular mechanisms of neurogenesis appear conserved across vertebrates, the EGL as a site of shh-driven transit amplification is not, and is therefore implicated as a key amniote innovation that facilitated the evolution of the elaborate foliated cerebella found in birds and mammals. Ellucidating the molecular mechanisms underlying the origin of the EGL in evolution could have significant impacts on our understanding of the molecular details of cerebellar development.

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. Wingate RJT, Hatten ME (1999) The role of the rhombic lip in avian cerebellum development. Development 126:4395–4404

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Falconer DS (1951) 2 New mutants, Trembler and Reeler, with neurological actions in the house mouse (Mus musculus L). Journal of Genetics 50:192–201

    Article  Google Scholar 

  4. Rakic P, Sidman RL (1973) Weaver mutant mouse cerebellum: defective neuronal migration secondary to abnormality of Bergmann glia. Proc Natl Acad Sci U S A 70:240–244

    Article  CAS  PubMed  Google Scholar 

  5. Chaplin N, Tendeng C, Wingate RJ (2010) Absence of an external germinal layer in zebrafish and shark reveals a distinct, anamniote ground plan of cerebellum development. J Neurosci 30:3048–3057

    Article  CAS  PubMed  Google Scholar 

  6. Kani S, Bae YK, Shimizu T, Tanabe K, Satou C, Parsons MJ, Scott E, Higashijima S, Hibi M (2010) Proneural gene-linked neurogenesis in zebrafish cerebellum. Dev Biol 343:1–17

    Article  CAS  PubMed  Google Scholar 

  7. Kaslin J, Ganz J, Geffarth M, Grandel H, Hans S, Brand M (2009) Stem cells in the adult zebrafish cerebellum: initiation and maintenance of a novel stem cell niche. J Neurosci 29:6142–6153

    Article  CAS  PubMed  Google Scholar 

  8. Alder J, Lee KJ, Jessell TM, Hatten ME (1999) Generation of cerebellar granule neurons in vivo by transplantation of BMP-treated neural progenitor cells. Nat Neurosci 2:535–540

    Article  CAS  PubMed  Google Scholar 

  9. Helms AW, Johnson JE (2003) Specification of dorsal spinal cord interneurons. Curr Opin Neurobiol 13:42–49

    Article  CAS  PubMed  Google Scholar 

  10. Chizhikov VV, Lindgren AG, Currle DS, Rose MF, Monuki ES, Millen KJ (2006) The roof plate regulates cerebellar cell-type specification and proliferation. Development 133:2793–2804

    Article  CAS  PubMed  Google Scholar 

  11. Lee KJ, Dietrich P, Jessell TM (2000) Genetic ablation reveals that the roof plate is essential for dorsal interneuron specification. Nature 403:734–740

    Article  CAS  PubMed  Google Scholar 

  12. Millonig JH, Millen KJ, Hatten ME (2000) The mouse Dreher gene Lmx1a controls formation of the roof plate in the vertebrate CNS [see comments]. Nature 403:764–769

    Article  CAS  PubMed  Google Scholar 

  13. 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  CAS  PubMed  Google Scholar 

  14. Ben-Arie N, Bellen HJ, Armstrong DL, McCall AE, Gordadze PR, Guo Q, Matzuk MM, Zoghbi HY (1997) Math1 is essential for genesis of cerebellar granule neurons. Nature 390:169–172

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Rose MF, Ahmad KA, Thaller C, Zoghbi HY (2009) Excitatory neurons of the proprioceptive, interoceptive, and arousal hindbrain networks share a developmental requirement for Math1. Proc Natl Acad Sci U S A 106:22462–22467

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Wang VY, Zoghbi HY (2001) Genetic regulation of cerebellar development. Nat Rev Neurosci 2:484–491

    Article  CAS  PubMed  Google Scholar 

  19. Bermingham NA, Hassan BA, Wang VY, Fernandez M, Banfi S, Bellen HJ, Fritzsch B, Zoghbi HY (2001) Proprioceptor pathway development is dependent on Math1. Neuron 30:411–422

    Article  CAS  PubMed  Google Scholar 

  20. Glasgow SM, Henke RM, Macdonald RJ, Wright CV, Johnson JE (2005) Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn. Development 132:5461–5469

    Article  CAS  PubMed  Google Scholar 

  21. Helms AW, Johnson JE (1998) Progenitors of dorsal commissural interneurons are defined by MATH1 expression. Development 125:919–928

    CAS  PubMed  Google Scholar 

  22. Miesegaes GR, Klisch TJ, Thaller C, Ahmad KA, Atkinson RC, Zoghbi HY (2009) Identification and subclassification of new Atoh1 derived cell populations during mouse spinal cord development. Dev Biol 327:339–351

    Article  CAS  PubMed  Google Scholar 

  23. Zordan P, Croci L, Hawkes R, Consalez GG (2008) Comparative analysis of proneural gene expression in the embryonic cerebellum. Dev Dyn 237:1726–1735

    Article  CAS  PubMed  Google Scholar 

  24. Morales D, Hatten ME (2006) Molecular markers of neuronal progenitors in the embryonic cerebellar anlage. J Neurosci 26:12226–12236

    Article  CAS  PubMed  Google Scholar 

  25. Gilthorpe JD, Papantoniou EK, Chedotal A, Lumsden A, Wingate RJ (2002) The migration of cerebellar rhombic lip derivatives. Development 129:4719–4728

    CAS  PubMed  Google Scholar 

  26. 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  CAS  PubMed  Google Scholar 

  27. Chédotal A (2010) Should I stay or should I go? Becoming a granule cell. Trends Neurosci 33:163–172

    Article  PubMed  Google Scholar 

  28. Lu Q, Sun EE, Klein RS, Flanagan JG (2001) Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction. Cell 105:69–79

    Article  CAS  PubMed  Google Scholar 

  29. Zhou P, Porcionatto M, Pilapil M, Chen Y, Choi Y, Tolias KF, Bikoff JB, Hong EJ, Greenberg ME, Segal RA (2007) Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55:53–68

    Article  CAS  PubMed  Google Scholar 

  30. Zhu Y, Yu T, Rao Y (2004) Temporal regulation of cerebellar EGL migration through a switch in cellular responsiveness to the meninges. Dev Biol 267:153–164

    Article  CAS  PubMed  Google Scholar 

  31. Zhu Y, Yu T, Zhang XC, Nagasawa T, Wu JY, Rao Y (2002) Role of the chemokine SDF-1 as the meningeal attractant for embryonic cerebellar neurons. Nat Neurosci 5:719–720

    Article  CAS  PubMed  Google Scholar 

  32. Miale IL, Sidman RL (1961) An autographic analysis of histogenesis in the mouse cerebellum. Experimental Neurology 4:277–296

    Article  CAS  PubMed  Google Scholar 

  33. 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  CAS  PubMed  Google Scholar 

  34. Chizhikov VV, Lindgren AG, Mishima Y, Roberts RW, Aldinger KA, Miesegaes GR, Currle DS, Monuki ES, Millen KJ (2010) Lmx1a regulates fates and location of cells originating from the cerebellar rhombic lip and telencephalic cortical hem. Proc Natl Acad Sci U S A 107:10725–10730

    Article  CAS  PubMed  Google Scholar 

  35. Wilson LJ, Wingate RJ (2006) Temporal identity transition in the avian cerebellar rhombic lip. Dev Biol 297:508–521

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  37. 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  CAS  PubMed  Google Scholar 

  38. Wallace VA (1999) Purkinje cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Current Biology 9:445–448

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. Gold DA, Baek SH, Schork NJ, Rose DW, Larsen DD, Sachs BD, Rosenfeld MG, Hamilton BA (2003) RORalpha coordinates reciprocal signaling in cerebellar development through Sonic hedgehog and calcium-dependent pathways. Neuron 40:1119–1131

    Article  CAS  PubMed  Google Scholar 

  41. Espinosa JS, Luo L (2008) Timing neurogenesis and differentiation: insights from quantitative clonal analyses of cerebellar granule cells. J Neurosci 28:2301–2312

    Article  CAS  PubMed  Google Scholar 

  42. Flora A, Klisch TJ, Schuster G, Zoghbi HY (2009) Deletion of Atoh1 disrupts Sonic hedgehog signaling in the developing cerebellum and prevents medulloblastoma. Science 326:1424–1427

    Article  CAS  PubMed  Google Scholar 

  43. Zhao H, Ayrault O, Zindy F, Kim JH, Roussel MF (2008) Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development. Genes Dev 22:722–727

    Article  CAS  PubMed  Google Scholar 

  44. 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  CAS  PubMed  Google Scholar 

  45. 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  CAS  PubMed  Google Scholar 

  46. 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  Google Scholar 

  47. Dubuc AM, Northcott PA, Kenney AM, Taylor MD (2010) Calculating a cure for cancer: managing medulloblastoma MATH1-ematically. Expert Rev Neurother 10:1489–1492

    Article  PubMed  Google Scholar 

  48. Goodrich LV, Milenkovi L, Higgins KM, Scott MP (2010) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277:1109–13.

    Google Scholar 

  49. Schuller U, Heine VM, Mao J, Kho AT, Dillon AK, Han YG, Huillard E, Sun T, Ligon AH, Qian Y et al (2008) Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14:123–134

    Article  CAS  PubMed  Google Scholar 

  50. Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M, Schuller U, Machold R, Fishell G, Rowitch DH et al (2008) Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14:135–145

    Article  CAS  PubMed  Google Scholar 

  51. Lee EY, Ji H, Ouyang Z, Zhou B, Ma W, Vokes SA, McMahon AP, Wong WH, Scott MP (2010) Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis. Proc Natl Acad Sci U S A 107:0736–9741.

    Google Scholar 

  52. Kriegstein A, Noctor S, Martinez-Cerdeno V (2006) Patterns of neural stem and progenitor cell division may underlie evolutionary cortical expansion. Nat Rev Neurosci 7:883–890

    Article  CAS  PubMed  Google Scholar 

  53. Noctor SC, Martinez-Cerdeno V, Ivic L, Kriegstein AR (2004) Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci 7:136–144

    Article  CAS  PubMed  Google Scholar 

  54. Hansen DV, Lui JH, Parker PR, Kriegstein AR (2010) Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464:554–561

    Article  CAS  PubMed  Google Scholar 

  55. Nieuwenhuys R, ten Donkelaar HJ, Nicholson C (1998) The central nervous system of vertebrates. Springer, Berlin

    Google Scholar 

  56. Yopak KE, Lisney TJ, Collin SP, Montgomery JC (2007) Variation in brain organization and cerebellar foliation in chondrichthyans: sharks and holocephalans. Brain Behav Evol 69:280–300

    Article  PubMed  Google Scholar 

  57. Lisney TJ, Yopak KE, Montgomery JC, Collin SP (2008) Variation in brain organization and cerebellar foliation in chondrichthyans: batoids. Brain Behav Evol 72:262–282

    Article  PubMed  Google Scholar 

  58. Yopak KE, Montgomery JC (2008) Brain organization and specialization in deep-sea chondrichthyans. Brain Behav Evol 71:287–304

    Article  PubMed  Google Scholar 

  59. Grandel H, Kaslin J, Ganz J, Wenzel I, Brand M (2006) Neural stem cells and neurogenesis in the adult zebrafish brain: origin, proliferation dynamics, migration and cell fate. Dev Biol 295:263–277

    Article  CAS  PubMed  Google Scholar 

  60. Sultan F, Glickstein M (2007) The cerebellum: comparative and animal studies. Cerebellum 6:168–176

    Article  PubMed  Google Scholar 

  61. Rodriguez-Moldes I, Ferreiro-Galve S, Carrera I, Sueiro C, Candal E, Mazan S, Anadon R (2008) Development of the cerebellar body in sharks: spatiotemporal relations of Pax6 expression, cell proliferation and differentiation. Neurosci Lett 432:105–110

    CAS  PubMed  Google Scholar 

  62. Miyata T, Maeda T, Lee JE (1999) NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. Genes Dev 13:1647–1652

    Article  CAS  PubMed  Google Scholar 

  63. Koster RW, Fraser SE (2006) FGF signaling mediates regeneration of the differentiating cerebellum through repatterning of the anterior hindbrain and reinitiation of neuronal migration. J Neurosci 26:7293–7304

    Article  PubMed  Google Scholar 

  64. Rieger S, Senghaas N, Walch A, Koster RW (2009) Cadherin-2 controls directional chain migration of cerebellar granule neurons. PLoS Biol 7:e1000240

    Article  PubMed  Google Scholar 

  65. Volkmann K, Rieger S, Babaryka A, Koster RW (2008) The zebrafish cerebellar rhombic lip is spatially patterned in producing granule cell populations of different functional compartments. Dev Biol 313:167–180

    Article  CAS  PubMed  Google Scholar 

  66. Gona AG (1972) Morphogenesis of the cerebellum of the frog tadpole during spontaneous metamorphosis. J Comp Neurol 146:133–142

    Article  CAS  PubMed  Google Scholar 

  67. Gans C, Northcutt RG (1983) Neural crest and the origin of vertebrates: a new head. Science 220:268–273

    Article  CAS  PubMed  Google Scholar 

  68. Putnam NH, Butts T, Ferrier DE, Furlong RF, Hellsten U, Kawashima T, Robinson-Rechavi M, Shoguchi E, Terry A, Yu JK et al (2008) The amphioxus genome and the evolution of the chordate karyotype. Nature 453:1064–1071

    Article  CAS  PubMed  Google Scholar 

  69. Delsuc F, Brinkmann H, Chourrout D, Philippe H (2006) Tunicates and not cephalochordates are the closest living relatives of vertebrates. Nature 439:965–968

    Article  CAS  PubMed  Google Scholar 

  70. Holland LZ (2009) Chordate roots of the vertebrate nervous system: expanding the molecular toolkit. Nat Rev Neurosci 10:736–746

    Article  CAS  PubMed  Google Scholar 

  71. Lowe CJ, Terasaki M, Wu M, Freeman RM Jr, Runft L, Kwan K, Haigo S, Aronowicz J, Lander E, Gruber C et al (2006) Dorsoventral patterning in hemichordates: insights into early chordate evolution. PLoS Biol 4:e291

    Article  PubMed  Google Scholar 

  72. Lowe CJ, Wu M, Salic A, Evans L, Lander E, Stange-Thomann N, Gruber CE, Gerhart J, Kirschner M (2003) Anteroposterior patterning in hemichordates and the origins of the chordate nervous system. Cell 113:853–865

    Article  CAS  PubMed  Google Scholar 

  73. Denes AS, Jekely G, Steinmetz PR, Raible F, Snyman H, Prud'homme B, Ferrier DE, Balavoine G, Arendt D (2007) Molecular architecture of annelid nerve cord supports common origin of nervous system centralization in bilateria. Cell 129:277–288

    Article  CAS  PubMed  Google Scholar 

  74. Tomer R, Denes AS, Tessmar-Raible K, Arendt D (2010) Profiling by image registration reveals common origin of annelid mushroom bodies and vertebrate pallium. Cell 142:800–809

    Article  CAS  PubMed  Google Scholar 

  75. Huang X, Ketova T, Fleming JT, Wang H, Dey SK, Litingtung Y, Chiang C (2009) Sonic hedgehog signaling regulates a novel epithelial progenitor domain of the hindbrain choroid plexus. Development 136:2535–2543

    Article  CAS  PubMed  Google Scholar 

  76. 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 U S A 107:8422–8427

    Article  CAS  PubMed  Google Scholar 

  77. Nielsen CM, Dymecki SM (2010) Sonic hedgehog is required for vascular outgrowth in the hindbrain choroid plexus. Dev Biol 340:430–437

    Article  CAS  PubMed  Google Scholar 

  78. Helms AW, Abney AL, Ben-Arie N, Zoghbi HY, Johnson JE (2000) Autoregulation and multiple enhancers control Math1 expression in the developing nervous system. Development 127:1185–1196

    CAS  PubMed  Google Scholar 

  79. Lumpkin EA, Collisson T, Parab P, Omer-Abdalla A, Haeberle H, Chen P, Doetzlhofer A, White P, Groves A, Segil N et al (2003) Math1-driven GFP expression in the developing nervous system of transgenic mice. Gene Expr Patterns 3:389–395

    Article  CAS  PubMed  Google Scholar 

  80. Ebert PJ, Timmer JR, Nakada Y, Helms AW, Parab PB, Liu Y, Hunsaker TL, Johnson JE (2003) Zic1 represses Math1 expression via interactions with the Math1 enhancer and modulation of Math1 autoregulation. Development 130:1949–1959

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thomas Butts.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Butts, T., Chaplin, N. & Wingate, R.J.T. Can Clues from Evolution Unlock the Molecular Development of the Cerebellum?. Mol Neurobiol 43, 67–76 (2011). https://doi.org/10.1007/s12035-010-8160-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-010-8160-2

Keywords

Navigation