Early Purkinje Cell Development and the Origins of Cerebellar Patterning

  • Filippo Casoni
  • Laura Croci
  • Ottavio Cremona
  • Richard HawkesEmail author
  • G. Giacomo ConsalezEmail author
Part of the Contemporary Clinical Neuroscience book series (CCNE)


This chapter explores the mechanisms that regulate Purkinje cell neurogenesis, revealing the finely timed contribution of many regulatory genes in the control of PC progenitor specification, proliferation, subtype differentiation, migration, and survival from the cerebellar primordium to the end of prenatal embryogenesis, discussing some of the key molecules involved and the ways they combine to generate the complex adult cerebellar architecture.


Zebrin Transverse zone Stripe Ventricular zone Ebf2 Reelin 



The authors’ research is funded through grants provided by the Italian Telethon Foundation (to GGC) and by the Italian Ministry of Health (to OC).


  1. 1.
    Hawkes R, Gravel C. The modular cerebellum. Prog Neurobiol. 1991;36(4):309–27. PubMed PMID: 1871318.PubMedCrossRefGoogle Scholar
  2. 2.
    Hawkes R. An anatomical model of cerebellar modules. Prog Brain Res. 1997;114:39–52. PubMed PMID: 9193137.PubMedCrossRefGoogle Scholar
  3. 3.
    Eisenman LM. Antero-posterior boundaries and compartments in the cerebellum: evidence from selected neurological mutants. Prog Brain Res. 2000;124:23–30. PubMed PMID: 10943114.PubMedCrossRefGoogle Scholar
  4. 4.
    Sillitoe R, Joyner A. Morphology, molecular codes, and circuitry produce the three-dimensional complexity of the cerebellum. Annu Rev Cell Dev Biol. 2007;23:549–77. Epub ahead of print.PubMedCrossRefGoogle Scholar
  5. 5.
    Apps R, Hawkes R. Cerebellar cortical organization: a one-map hypothesis. Nat Rev Neurosci. 2009;10(9):670–81. PubMed PMID: 19693030. Epub 2009/08/21. eng.PubMedCrossRefGoogle Scholar
  6. 6.
    Armstrong CL, Hawkes R. Pattern formation in the cerebellum. San Rafael: Morgan and Claypool; 2013.CrossRefGoogle Scholar
  7. 7.
    Brochu G, Maler L, Hawkes R. Zebrin II: a polypeptide antigen expressed selectively by Purkinje cells reveals compartments in rat and fish cerebellum. J Comp Neurol. 1990;291(4):538–52. PubMed PMID: 2329190.PubMedCrossRefGoogle Scholar
  8. 8.
    Ahn AH, Dziennis S, Hawkes R, Herrup K. The cloning of zebrin II reveals its identity with aldolase C. Development. 1994;120(8):2081–90. PubMed PMID: 7925012.PubMedGoogle Scholar
  9. 9.
    Voogd J, Ruigrok TJ. The organization of the corticonuclear and olivocerebellar climbing fiber projections to the rat cerebellar vermis: the congruence of projection zones and the zebrin pattern. J Neurocytol. 2004;33(1):5–21. PubMed PMID: 15173629.PubMedCrossRefGoogle Scholar
  10. 10.
    Sillitoe RV, Chung SH, Fritschy JM, Hoy M, Hawkes R. Golgi cell dendrites are restricted by Purkinje cell stripe boundaries in the adult mouse cerebellar cortex. J Neurosci. 2008;28(11):2820–6. PubMed PMID: 18337412.PubMedCrossRefGoogle Scholar
  11. 11.
    Consalez GG, Hawkes R. The compartmental restriction of cerebellar interneurons. Front Neural Circ. 2012;6:123. PubMed PMID: 23346049. Pubmed Central PMCID: 3551280. Epub 2013/01/25.Google Scholar
  12. 12.
    Scott TG. A unique pattern of localization within the cerebellum. Nature. 1963;200:793. PubMed PMID: 14087025.PubMedCrossRefGoogle Scholar
  13. 13.
    Ramó y Cajal S. Histologie du Système Nerveux de l’Homme et des Vertébrés. 1911.Google Scholar
  14. 14.
    Hatten ME, Heintz N. Mechanisms of neural patterning and specification in the developing cerebellum. Ann Rev Neurosci. 1995;18:385–408.PubMedCrossRefGoogle Scholar
  15. 15.
    Altman J, Bayer SA. Development of the cerebellar system in relation to its evolution, structure, and functions. Boca Raton: CRC Press; 1997.Google Scholar
  16. 16.
    Sotelo C. Cellular and genetic regulation of the development of the cerebellar system. Prog Neurobiol. 2004;72(5):295–339. PubMed PMID: 15157725.PubMedCrossRefGoogle Scholar
  17. 17.
    Carletti B, Rossi F. Neurogenesis in the cerebellum. Neuroscientist. 2008;14(1):91–100. PubMed PMID: 17911211. Epub 2007/10/04. eng.PubMedCrossRefGoogle Scholar
  18. 18.
    Hoshino M. Neuronal subtype specification in the cerebellum and dorsal hindbrain. Develop Growth Differ. 2012;54(3):317–26. PubMed PMID: 22404503.CrossRefGoogle Scholar
  19. 19.
    Leto K, Arancillo M, Becker EB, Buffo A, Chiang C, Ding B, et al. Consensus paper: cerebellar develpoment. Cerebellum. 2015;15:789–828. PubMed PMID: 26439486. Pubmed Central PMCID: PMC4846577.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Smeyne RJ, Chu T, Lewin A, Bian F, Sanlioglu SC, Kunsch C, et al. Local control of granule cell generation by cerebellar Purkinje cells. Mol Cell Neurosci. 1995;6(3):230–51.PubMedCrossRefGoogle Scholar
  21. 21.
    Wechsler-Reya RJ, Scott MP. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron. 1999;22(1):103–14. PubMed PMID: 10027293.PubMedCrossRefGoogle Scholar
  22. 22.
    Dahmane N, Ruiz-i-Altaba A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development. 1999;126(14):3089–100.PubMedGoogle Scholar
  23. 23.
    Wallace VA. Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol. 1999;9:445–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Goffinet AM. The embryonic development of the cerebellum in normal and reeler mutant mice. Anat Embryol (Berl). 1983;168(1):73–86. PubMed PMID: 6650858.CrossRefGoogle Scholar
  25. 25.
    Paradies MA, Eisenman LM. Evidence of early topographic organization in the embryonic olivocerebellar projection: a model system for the study of pattern formation processes in the central nervous system. Dev Dyn. 1993;197(2):125–45. PubMed PMID: 8219355.PubMedCrossRefGoogle Scholar
  26. 26.
    Grishkat HL, Eisenman LM. Development of the spinocerebellar projection in the prenatal mouse. J Comp Neurol. 1995;363(1):93–108. PubMed PMID: 8682940.PubMedCrossRefGoogle Scholar
  27. 27.
    White JJ, Sillitoe RV. Postnatal development of cerebellar zones revealed by neurofilament heavy chain protein expression. Front Neuroanat. 2013;7:9. PubMed PMID: 23675325. Pubmed Central PMCID: PMC3648691.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Sillitoe RV, Gopal N, Joyner AL. Embryonic origins of ZebrinII parasagittal stripes and establishment of topographic Purkinje cell projections. Neuroscience. 2009;162(3):574–88. PubMed PMID: 19150487. Pubmed Central PMCID: 2716412. Epub 2009/01/20. eng.PubMedCrossRefGoogle Scholar
  29. 29.
    Blatt GJ, Eisenman LM. Topographic and zonal organization of the olivocerebellar projection in the reeler mutant mouse. J Comp Neurol. 1988;267(4):603–15. PubMed PMID: 2831252.PubMedCrossRefGoogle Scholar
  30. 30.
    Reeber SL, Loeschel CA, Franklin A, Sillitoe RV. Establishment of topographic circuit zones in the cerebellum of scrambler mutant mice. Front Neural Circ. 2013;7:122. PubMed PMID: 23885237. Pubmed Central PMCID: PMC3717479.Google Scholar
  31. 31.
    Sillitoe RV, Vogel MW, Joyner AL. Engrailed homeobox genes regulate establishment of the cerebellar afferent circuit map. J Neurosci. 2010;30(30):10015–24. PubMed PMID: 20668186. Pubmed Central PMCID: PMC2921890.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Hallonet ME, Teillet MA, Le Douarin NM. A new approach to the development of the cerebellum provided by the quail-chick marker system. Development. 1990;108(1):19–31. PubMed PMID: 2351063. Epub 1990/01/01. eng.PubMedGoogle Scholar
  33. 33.
    Hallonet ME, Le Douarin NM. Tracing neuroepithelial cells of the mesencephalic and metencephalic alar plates during cerebellar ontogeny in quail-chick chimaeras. Eur J Neurosci. 1993;5(9):1145–55.PubMedCrossRefGoogle Scholar
  34. 34.
    Hallonet M, Alvarado-Mallart RM. The chick/quail chimeric system: a model for early cerebellar development. Perspect Dev Neurobiol. 1997;5(1):17–31. PubMed PMID: 9509515.PubMedGoogle Scholar
  35. 35.
    Broccoli V, Boncinelli E, Wurst W. The caudal limit of Otx2 expression positions the isthmic organizer. Nature. 1999;9(401(6749)):164–8.CrossRefGoogle Scholar
  36. 36.
    Li JY, Lao Z, Joyner AL. New regulatory interactions and cellular responses in the isthmic organizer region revealed by altering Gbx2 expression. Development. 2005;132(8):1971–81. PubMed PMID: 15790971.PubMedCrossRefGoogle Scholar
  37. 37.
    Martinez S, Wassef M, Alvarado-Mallart RM. Induction of a mesencephalic phenotype in the 2-day-old chick prosencephalon is preceded by the early expression of the homeobox gene en. Neuron. 1991;6(6):971–81. PubMed PMID: 1675863.PubMedCrossRefGoogle Scholar
  38. 38.
    Martinez S, Crossley PH, Cobos I, Rubenstein JL, Martin GR. FGF8 induces formation of an ectopic isthmic organizer and isthmocerebellar development via a repressive effect on Otx2 expression. Development. 1999;126(6):1189–200. PubMed PMID: 10021338.PubMedGoogle Scholar
  39. 39.
    Martinez S, Alvarado-Mallart RM. Rostral cerebellum originates from the caudal portion of the so-called ‘Mesencephalic’ vesicle: a study using chick/quail chimeras. Eur J Neurosci. 1989;1(6):549–60. PubMed PMID: 12106114. Epub 1989/01/01. Eng.PubMedCrossRefGoogle Scholar
  40. 40.
    Alvarez Otero R, Sotelo C, Alvarado-Mallart RM. Chick/quail chimeras with partial cerebellar grafts: an analysis of the origin and migration of cerebellar cells. J Comp Neurol. 1993;333(4):597–615. PubMed PMID: 7690372. Epub 1993/07/22. eng.PubMedCrossRefGoogle Scholar
  41. 41.
    Marin F, Puelles L. Patterning of the embryonic avian midbrain after experimental inversions: a polarizing activity from the isthmus. Dev Biol. 1994;163:19–37.PubMedCrossRefGoogle Scholar
  42. 42.
    Hidalgo-Sanchez M, Millet S, Bloch-Gallego E, Alvarado-Mallart RM. Specification of the meso-isthmo-cerebellar region: the Otx2/Gbx2 boundary. Brain Res Brain Res Rev. 2005;49(2):134–49. PubMed PMID: 16111544.PubMedCrossRefGoogle Scholar
  43. 43.
    Hoshino M, Nakamura S, Mori K, Kawauchi T, Terao M, Nishimura YV, et al. Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron. 2005;47(2):201–13. PubMed PMID: 16039563.PubMedCrossRefGoogle Scholar
  44. 44.
    Akazawa C, Ishibashi M, Shimizu C, Nakanishi S, Kageyama R. 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. 1995;270(15):8730–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Anthony TE, Klein C, Fishell G, Heintz N. Radial glia serve as neuronal progenitors in all regions of the central nervous system. Neuron. 2004;41(6):881–90. PubMed PMID: 15046721.PubMedCrossRefGoogle Scholar
  46. 46.
    Seto Y, Nakatani T, Masuyama N, Taya S, Kumai M, Minaki Y, et al. Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum. Nat Commun. 2014;5:3337. PubMed PMID: 24535035.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Yamada M, Seto Y, Taya S, Owa T, Inoue YU, Inoue T, et al. Specification of spatial identities of cerebellar neuron progenitors by ptf1a and atoh1 for proper production of GABAergic and glutamatergic neurons. J Neurosci. 2014;34(14):4786–800. PubMed PMID: 24695699.PubMedCrossRefGoogle Scholar
  48. 48.
    Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, Coleman RJ, Garrett C, et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet. 2004;36(12):1301–5. PubMed PMID: 15543146.PubMedCrossRefGoogle Scholar
  49. 49.
    Alder J, Cho NK, Hatten ME. Embryonic precursor cells from the rhombic lip are specified to a cerebellar granule neuron identity. Neuron. 1996;17(3):389–99. PubMed PMID: 8816703.PubMedCrossRefGoogle Scholar
  50. 50.
    Wingate RJ. The rhombic lip and early cerebellar development. Curr Opin Neurobiol. 2001;11(1):82–8. PubMed PMID: 11179876. Epub 2001/02/17. eng.PubMedCrossRefGoogle Scholar
  51. 51.
    Machold R, Fishell G. Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron. 2005;48(1):17–24. PubMed PMID: 16202705.PubMedCrossRefGoogle Scholar
  52. 52.
    Wang VY, Rose MF, Zoghbi HY. Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron. 2005;48(1):31–43. PubMed PMID: 16202707.PubMedCrossRefGoogle Scholar
  53. 53.
    Fink AJ, Englund C, Daza RA, Pham D, Lau C, Nivison M, et al. Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip. J Neurosci. 2006;26(11):3066–76. PubMed PMID: 16540585.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Englund C, Kowalczyk T, Daza RA, Dagan A, Lau C, Rose MF, et al. Unipolar brush cells of the cerebellum are produced in the rhombic lip and migrate through developing white matter. J Neurosci. 2006;26(36):9184–95. PubMed PMID: 16957075PubMedCrossRefGoogle Scholar
  55. 55.
    Vong KI, Leung CK, Behringer RR, Kwan KM. Sox9 is critical for suppression of neurogenesis but not initiation of gliogenesis in the cerebellum. Mol Brain. 2015;8:25. PubMed PMID: 25888505. Pubmed Central PMCID: PMC4406026.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Machold RP, Kittell DJ, Fishell GJ. Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip. Neural Develop. 2007;2:5. PubMed PMID: 17319963.PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Masserdotti G, Badaloni A, Green YS, Croci L, Barili V, Bergamini G, et al. ZFP423 coordinates Notch and bone morphogenetic protein signaling, selectively up-regulating Hes5 gene expression. J Biol Chem. 2010;285(40):30814–24. PubMed PMID: 20547764. Pubmed Central PMCID: 2945575.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Miale IL, Sidman RL. An autoradiographic analysis of histogenesis in the mouse cerebellum. Exp Neurol. 1961;4:277–96. PubMed PMID: 14473282.PubMedCrossRefGoogle Scholar
  59. 59.
    Sekerkova G, Ilijic E, Mugnaini E. Time of origin of unipolar brush cells in the rat cerebellum as observed by prenatal bromodeoxyuridine labeling. Neuroscience. 2004;127(4):845–58. PubMed PMID: 15312897.PubMedCrossRefGoogle Scholar
  60. 60.
    Kim EJ, Battiste J, Nakagawa Y, Johnson JE. Ascl1 (Mash1) lineage cells contribute to discrete cell populations in CNS architecture. Mol Cell Neurosci. 2008;38(4):595–606. PubMed PMID: 18585058. Epub 2008/07/01. eng.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Chizhikov VV, Lindgren AG, Currle DS, Rose MF, Monuki ES, Millen KJ. The roof plate regulates cerebellar cell-type specification and proliferation. Development. 2006;133(15):2793–804. PubMed PMID: 16790481.PubMedCrossRefGoogle Scholar
  62. 62.
    Leto K, Carletti B, Williams IM, Magrassi L, Rossi F. Different types of cerebellar GABAergic interneurons originate from a common pool of multipotent progenitor cells. J Neurosci: Off J Soc Neurosci. 2006;26(45):11682–94. PubMed PMID: 17093090. Epub 2006/11/10. eng.CrossRefGoogle Scholar
  63. 63.
    Leto K, Rossi F. Specification and differentiation of cerebellar GABAergic neurons. Cerebellum. 2012;11(2):434–5. PubMed PMID: 22090364.PubMedCrossRefGoogle Scholar
  64. 64.
    Ju J, Liu Q, Zhang Y, Liu Y, Jiang M, Zhang L, et al. Olig2 regulates Purkinje cell generation in the early developing mouse cerebellum. Sci Rep. 2016;6:30711. PubMed PMID: 27469598. Pubmed Central PMCID: PMC4965836.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Mizuhara E, Minaki Y, Nakatani T, Kumai M, Inoue T, Muguruma K, et al. Purkinje cells originate from cerebellar ventricular zone progenitors positive for Neph3 and E-cadherin. Dev Biol. 2009. PubMed PMID: 20004188. Epub 2009/12/17. Eng.Google Scholar
  66. 66.
    Minaki Y, Nakatani T, Mizuhara E, Inoue T, Ono Y. Identification of a novel transcriptional corepressor, Corl2, as a cerebellar Purkinje cell-selective marker. Gene Expr Patterns. 2008;8(6):418–23. PubMed PMID: 18522874. Epub 2008/06/05. eng.PubMedCrossRefGoogle Scholar
  67. 67.
    Mizuhara E, Nakatani T, Minaki Y, Sakamoto Y, Ono Y. Corl1, a novel neuronal lineage-specific transcriptional corepressor for the homeodomain transcription factor Lbx1. J Biol Chem. 2005;280(5):3645–55. PubMed PMID: 15528197.PubMedCrossRefGoogle Scholar
  68. 68.
    Morales D, Hatten ME. Molecular markers of neuronal progenitors in the embryonic cerebellar anlage. J Neurosci. 2006;26:12226–36.PubMedCrossRefGoogle Scholar
  69. 69.
    Zordan P, Croci L, Hawkes R, Consalez GG. Comparative analysis of proneural gene expression in the embryonic cerebellum. Dev Dyn. 2008;237(6):1726–35. PubMed PMID: 18498101. Epub 2008/05/24. eng.PubMedCrossRefGoogle Scholar
  70. 70.
    Kim EJ, Hori K, Wyckoff A, Dickel LK, Koundakjian EJ, Goodrich LV, et al. Spatiotemporal fate map of neurogenin1 (Neurog1) lineages in the mouse central nervous system. J Comp Neurol. 2011;519(7):1355–70. PubMed PMID: 21452201. Epub 2011/04/01. eng.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Lundell TG, Zhou Q, Doughty ML. Neurogenin1 expression in cell lineages of the cerebellar cortex in embryonic and postnatal mice. Dev Dyn. 2009;238(12):3310–25. PubMed PMID: 19924827. Epub 2009/11/20. eng.PubMedCrossRefGoogle Scholar
  72. 72.
    Florio M, Leto K, Muzio L, Tinterri A, Badaloni A, Croci L, et al. Neurogenin 2 regulates progenitor cell-cycle progression and Purkinje cell dendritogenesis in cerebellar development. Development. 2012;139(13):2308–20. PubMed PMID: 22669821. Pubmed Central PMCID: 3367442. Epub 2012/06/07. eng.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Sarna JR, Marzban H, Watanabe M, Hawkes R. Complementary stripes of phospholipase Cbeta3 and Cbeta4 expression by Purkinje cell subsets in the mouse cerebellum. J Comp Neurol. 2006;496(3):303–13. PubMed PMID: 16566000.PubMedCrossRefGoogle Scholar
  74. 74.
    Armstrong CL, Krueger-Naug AM, Currie RW, Hawkes R. Constitutive expression of the 25-kDa heat shock protein Hsp25 reveals novel parasagittal bands of Purkinje cells in the adult mouse cerebellar cortex. J Comp Neurol. 2000;416(3):383–97. PubMed PMID: 10602096.PubMedCrossRefGoogle Scholar
  75. 75.
    Seil FJ, Johnson ML, Hawkes R. Molecular compartmentation expressed in cerebellar cultures in the absence of neuronal activity and neuron-glia interactions. J Comp Neurol. 1995;356(3):398–407. PubMed PMID: 7642801.PubMedCrossRefGoogle Scholar
  76. 76.
    Leclerc N, Gravel C, Hawkes R. Development of parasagittal zonation in the rat cerebellar cortex: MabQ113 antigenic bands are created postnatally by the suppression of antigen expression in a subset of Purkinje cells. J Comp Neurol. 1988;273(3):399–420. PubMed PMID: 2463281.PubMedCrossRefGoogle Scholar
  77. 77.
    Wassef M, Sotelo C, Thomasset M, Granholm AC, Leclerc N, Rafrafi J, et al. Expression of compartmentation antigen zebrin I in cerebellar transplants. J Comp Neurol. 1990;294(2):223–34. PubMed PMID: 2332530.PubMedCrossRefGoogle Scholar
  78. 78.
    Baader SL, Vogel MW, Sanlioglu S, Zhang X, Oberdick J. Selective disruption of “late onset” sagittal banding patterns by ectopic expression of engrailed-2 in cerebellar Purkinje cells. J Neurosci. 1999;19(13):5370–9. PubMed PMID: 10377347.PubMedCrossRefGoogle Scholar
  79. 79.
    Mathis L, Bonnerot C, Puelles L, Nicolas JF. Retrospective clonal analysis of the cerebellum using genetic laacZ/lacZ mouse mosaics. Development. 1997;124(20):4089–104. PubMed PMID: 9374405. Epub 1997/11/28. eng.PubMedGoogle Scholar
  80. 80.
    Hawkes R, Faulkner-Jones B, Tam P, Tan SS. Pattern formation in the cerebellum of murine embryonic stem cell chimeras. Eur J Neurosci. 1998;10(2):790–3. PubMed PMID: 9749745.PubMedCrossRefGoogle Scholar
  81. 81.
    Sgaier SK, Millet S, Villanueva MP, Berenshteyn F, Song C, Joyner AL. Morphogenetic and cellular movements that shape the mouse cerebellum; insights from genetic fate mapping. Neuron. 2005;45(1):27–40. PubMed PMID: 15629700.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Hashimoto M, Mikoshiba K. Mediolateral compartmentalization of the cerebellum is determined on the “birth date” of Purkinje cells. J Neurosci. 2003;23(36):11342–51. PubMed PMID: 14672998.PubMedCrossRefGoogle Scholar
  83. 83.
    Larouche M, Hawkes R. From clusters to stripes: the developmental origins of adult cerebellar compartmentation. Cerebellum. 2006;5(2):77–88. PubMed PMID: 16818382.PubMedCrossRefGoogle Scholar
  84. 84.
    Karam SD, Burrows RC, Logan C, Koblar S, Pasquale EB, Bothwell M. Eph receptors and ephrins in the developing chick cerebellum: relationship to sagittal patterning and granule cell migration. J Neurosci. 2000;20(17):6488–500. PubMed PMID: 10964955.PubMedCrossRefGoogle Scholar
  85. 85.
    Chung S-H, Marzban H, Croci L, Consalez G, Hawkes R. Purkinje cell subtype specification in the cerebellar cortex: Ebf2 acts to repress the Zebrin II-positive Purkinje cell phenotype. Neuroscience. 2008;153:721–32.PubMedCrossRefGoogle Scholar
  86. 86.
    Namba K, Sugihara I, Hashimoto M. Close correlation between the birth date of Purkinje cells and the longitudinal compartmentalization of the mouse adult cerebellum. J Comp Neurol. 2011;519(13):2594–614. PubMed PMID: 21456012.PubMedCrossRefGoogle Scholar
  87. 87.
    Malgaretti N, Pozzoli O, Bosetti A, Corradi A, Ciarmatori S, Panigada M, et al. Mmot1, a new helix-loop-helix transcription factor gene displaying a sharp expression boundary in the embryonic mouse brain. J Biol Chem. 1997;272(28):17632–9. PubMed PMID: 9211912. Epub 1997/07/11. engPubMedCrossRefGoogle Scholar
  88. 88.
    Dubois L, Vincent A. The COE – Collier/Olf1/EBF – transcription factors: structural conservation and diversity of developmental functions. Mech Dev. 2001;108(1–2):3–12.PubMedCrossRefGoogle Scholar
  89. 89.
    Liberg D, Sigvardsson M, Akerblad P. The EBF/Olf/Collier family of transcription factors: regulators of differentiation in cells originating from all three embryonal germ layers. Mol Cell Biol. 2002;22(24):8389–97. PubMed PMID: 12446759. Pubmed Central PMCID: PMC139877.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Miyata T, Ono Y, Okamoto M, Masaoka M, Sakakibara A, Kawaguchi A, et al. Migration, early axonogenesis, and Reelin-dependent layer-forming behavior of early/posterior-born Purkinje cells in the developing mouse lateral cerebellum. Neural Dev. 2010;5:23. PubMed PMID: 20809939. Pubmed Central PMCID: 2942860. Epub 2010/09/03. eng.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Larouche M, Che P, Hawkes R. Neurogranin expression identifies a novel array of Purkinje cell parasagittal stripes during mouse cerebellar development. J Comp Neurol. 2006;494(2):215–27.PubMedCrossRefGoogle Scholar
  92. 92.
    Croci L, Chung SH, Masserdotti G, Gianola S, Bizzoca A, Gennarini G, et al. A key role for the HLH transcription factor EBF2COE2,O/E-3 in Purkinje neuron migration and cerebellar cortical topography. Development. 2006;133(14):2719–29. PubMed PMID: 16774995.PubMedCrossRefGoogle Scholar
  93. 93.
    Croci L, Barili V, Chia D, Massimino L, van Vugt R, Masserdotti G, et al. Local insulin-like growth factor I expression is essential for Purkinje neuron survival at birth. Cell Death Differ. 2011;18(1):48–59. PubMed PMID: 20596079. Pubmed Central PMCID: 3131878.PubMedCrossRefGoogle Scholar
  94. 94.
    Wassef M, Zanetta JP, Brehier A, Sotelo C. Transient biochemical compartmentalization of Purkinje cells during early cerebellar development. Dev Biol. 1985;111(1):129–37. PubMed PMID: 2993082.PubMedCrossRefGoogle Scholar
  95. 95.
    Millen KJ, Hui CC, Joyner AL. A role for En-2 and other murine homologues of Drosophila segment polarity genes in regulating positional information in the developing cerebellum. Development. 1995;121(12):3935–45. PubMed PMID: 8575294.PubMedGoogle Scholar
  96. 96.
    Dastjerdi FV, Consalez GG, Hawkes R. Pattern formation during development of the embryonic cerebellum. Front Neuroanat. 2012;6:10. PubMed PMID: 22493569. Pubmed Central PMCID: 3318227. Epub 2012/04/12. eng.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Sugihara I, Fujita H. Peri- and postnatal development of cerebellar compartments in the mouse. Cerebellum. 2013;12(3):325–7. PubMed PMID: 23335119.PubMedCrossRefGoogle Scholar
  98. 98.
    Fujita H, Sugihara I. FoxP2 expression in the cerebellum and inferior olive: development of the transverse stripe-shaped expression pattern in the mouse cerebellar cortex. J Comp Neurol. 2012;520(3):656–77. PubMed PMID: 21935935PubMedCrossRefGoogle Scholar
  99. 99.
    Dehay C, Kennedy H. Cell-cycle control and cortical development. Nat Rev Neurosci. 2007;8(6):438–50. PubMed PMID: 17514197.PubMedCrossRefGoogle Scholar
  100. 100.
    Rouse RV, Sotelo C. Grafts of dissociated cerebellar cells containing Purkinje cell precursors organize into zebrin I defined compartments. Exp Brain Res. 1990;82(2):401–7. PubMed PMID: 1704849.PubMedCrossRefGoogle Scholar
  101. 101.
    Redies C, Neudert F, Lin J. Cadherins in cerebellar development: translation of embryonic patterning into mature functional compartmentalization. Cerebellum. 2011;10(3):393–408. PubMed PMID: 20820976.PubMedCrossRefGoogle Scholar
  102. 102.
    Graus-Porta D, Blaess S, Senften M, Littlewood-Evans A, Damsky C, Huang Z, et al. Beta1-class integrins regulate the development of laminae and folia in the cerebral and cerebellar cortex. Neuron. 2001;31(3):367–79. PubMed PMID: 11516395.PubMedCrossRefGoogle Scholar
  103. 103.
    Ozol K, Hayden JM, Oberdick J, Hawkes R. Transverse zones in the vermis of the mouse cerebellum. J Comp Neurol. 1999;412(1):95–111. PubMed PMID: 10440712.PubMedCrossRefGoogle Scholar
  104. 104.
    Sillitoe RV, Marzban H, Larouche M, Zahedi S, Affanni J, Hawkes R. Conservation of the architecture of the anterior lobe vermis of the cerebellum across mammalian species. Prog Brain Res. 2005;148:283–97. PubMed PMID: 15661197.PubMedCrossRefGoogle Scholar
  105. 105.
    Marzban H, Hawkes R. On the architecture of the posterior zone of the cerebellum. Cerebellum. 2011;10(3):422–34. PubMed PMID: 20838950.PubMedCrossRefGoogle Scholar
  106. 106.
    Sillitoe RV, Hawkes R. Whole-mount immunohistochemistry: a high-throughput screen for patterning defects in the mouse cerebellum. J Histochem Cytochem. 2002;50(2):235–44. PubMed PMID: 11799142.PubMedCrossRefGoogle Scholar
  107. 107.
    Dastjerdi FV. Transverse boundaries in the embryonic cerebellar cortex of the mouse. Alberta: University of Calgary; 2012.Google Scholar
  108. 108.
    Eisenman LM, Brothers R. Rostral cerebellar malformation (rcm/rcm): a murine mutant to study regionalization of the cerebellum. J Comp Neurol. 1998;394(1):106–17. PubMed PMID: 9550145.PubMedCrossRefGoogle Scholar
  109. 109.
    Tano D, Napieralski JA, Eisenman LM, Messer A, Plummer J, Hawkes R. Novel developmental boundary in the cerebellum revealed by zebrin expression in the lurcher (Lc/+) mutant mouse. J Comp Neurol. 1992;323(1):128–36. PubMed PMID: 1430312.PubMedCrossRefGoogle Scholar
  110. 110.
    Beierbach E, Park C, Ackerman SL, Goldowitz D, Hawkes R. Abnormal dispersion of a Purkinje cell subset in the mouse mutant cerebellar deficient folia (cdf). J Comp Neurol. 2001;436(1):42–51. PubMed PMID: 11413545.PubMedCrossRefGoogle Scholar
  111. 111.
    Cho JH, Tsai MJ. Preferential posterior cerebellum defect in BETA2/NeuroD1 knockout mice is the result of differential expression of BETA2/NeuroD1 along anterior-posterior axis. Dev Biol. 2006;290(1):125–38. PubMed PMID: 16368089.PubMedCrossRefGoogle Scholar
  112. 112.
    Hawkes R, Beierbach E, Tan SS. Granule cell dispersion is restricted across transverse boundaries in mouse chimeras. Eur J Neurosci. 1999;11(11):3800–8. PubMed PMID: 10583469.PubMedCrossRefGoogle Scholar
  113. 113.
    Marzban H, Kim CT, Doorn D, Chung SH, Hawkes R. A novel transverse expression domain in the mouse cerebellum revealed by a neurofilament-associated antigen. Neuroscience. 2008;153:721–32.PubMedCrossRefGoogle Scholar
  114. 114.
    Marzban H, Sillitoe RV, Hoy M, Chung SH, Rafuse VF, Hawkes R. Abnormal HNK-1 expression in the cerebellum of an N-CAM null mouse. J Neurocytol. 2004;33(1):117–30. PubMed PMID: 15173636.PubMedCrossRefGoogle Scholar
  115. 115.
    Marzban H, Chung S, Watanabe M, Hawkes R. Phospholipase Cbeta4 expression reveals the continuity of cerebellar topography through development. J Comp Neurol. 2007;502(5):857–71. PubMed PMID: 17436294.PubMedCrossRefGoogle Scholar
  116. 116.
    Armstrong CL, Krueger-Naug AM, Currie RW, Hawkes R. Constitutive expression of heat shock protein HSP25 in the central nervous system of the developing and adult mouse. J Comp Neurol. 2001;434(3):262–74. PubMed PMID: 11331528.PubMedCrossRefGoogle Scholar
  117. 117.
    D’Arcangelo G. Reelin in the years: controlling neuronal migration and maturation in the mammalian brain. Adv Neurosci. 2014;2014:4–19.Google Scholar
  118. 118.
    Bock HH, May P. Canonical and non-canonical Reelin signaling. Front Cell Neurosci. 2016;10:166. PubMed PMID: 27445693. Pubmed Central PMCID: PMC4928174.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, et al. Reeler/disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell. 1999;97(6):689–701. PubMed PMID: 10380922.PubMedCrossRefGoogle Scholar
  120. 120.
    Hiesberger T, Trommsdorff M, Howell BW, Goffinet A, Mumby MC, Cooper JA, et al. Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron. 1999;24(2):481–9. PubMed PMID: 10571241.PubMedCrossRefGoogle Scholar
  121. 121.
    Strasser V, Fasching D, Hauser C, Mayer H, Bock HH, Hiesberger T, et al. Receptor clustering is involved in Reelin signaling. Mol Cell Biol. 2004;24(3):1378–86. PubMed PMID: 14729980. Pubmed Central PMCID: PMC321426.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Goldowitz D, Cushing RC, Laywell E, D’Arcangelo G, Sheldon M, Sweet HO, et al. Cerebellar disorganization characteristic of reeler in scrambler mutant mice despite presence of reelin. J Neurosci: Off J Soc Neurosci. 1997;17(22):8767–77. PubMed PMID: 9348346. Epub 1997/11/14. eng.CrossRefGoogle Scholar
  123. 123.
    Howell BW, Hawkes R, Soriano P, Cooper JA. Neuronal position in the developing brain is regulated by mouse disabled-1. Nature. 1997;389(6652):733–7. PubMed PMID: 9338785.PubMedCrossRefGoogle Scholar
  124. 124.
    Sheldon M, Rice DS, D’Arcangelo G, Yoneshima H, Nakajima K, Mikoshiba K, et al. Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature. 1997;389(6652):730–3. PubMed PMID: 9338784.PubMedCrossRefGoogle Scholar
  125. 125.
    Gallagher E, Howell BW, Soriano P, Cooper JA, Hawkes R. Cerebellar abnormalities in the disabled (mdab1-1) mouse. J Comp Neurol. 1998;402(2):238–51. PubMed PMID: 9845246.PubMedCrossRefGoogle Scholar
  126. 126.
    Rice DS, Sheldon M, D’Arcangelo G, Nakajima K, Goldowitz D, Curran T. Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. Development. 1998;125(18):3719–29. PubMed PMID: 9716537.PubMedGoogle Scholar
  127. 127.
    Howell BW, Gertler FB, Cooper JA. Mouse disabled (mDab1): a Src binding protein implicated in neuronal development. EMBO J. 1997;16(1):121–32. PubMed PMID: 9009273. Pubmed Central PMCID: PMC1169619.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Bock HH, Herz J. Reelin activates SRC family tyrosine kinases in neurons. Curr Biol. 2003;13(1):18–26. PubMed PMID: 12526740.PubMedCrossRefGoogle Scholar
  129. 129.
    Chung CY, Funamoto S, Firtel RA. Signaling pathways controlling cell polarity and chemotaxis. Trends Biochem Sci. 2001;26(9):557–66. PubMed PMID: 11551793.PubMedCrossRefGoogle Scholar
  130. 130.
    Larouche M, Beffert U, Herz J, Hawkes R. The Reelin receptors Apoer2 and Vldlr coordinate the patterning of Purkinje cell topography in the developing mouse cerebellum. PLoS One. 2008;3(2):e1653. PubMed PMID: 18301736. Pubmed Central PMCID: 2242849. Epub 2008/02/28. eng.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Hack I, Hellwig S, Junghans D, Brunne B, Bock HH, Zhao S, et al. Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons. Development. 2007;134(21):3883–91. PubMed PMID: 17913789.PubMedCrossRefGoogle Scholar
  132. 132.
    Ross ME, Fletcher C, Mason CA, Hatten ME, Heintz N. Meander tail reveals a discrete developmental unit in the mouse cerebellum. Proc Natl Acad Sci U S A. 1990;87(11):4189–92. PubMed PMID: 2349228. Pubmed Central PMCID: PMC54073.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Armstrong C, Hawkes R. Selective Purkinje cell ectopia in the cerebellum of the weaver mouse. J Comp Neurol. 2001;439(2):151–61. PubMed PMID: 11596045.PubMedCrossRefGoogle Scholar
  134. 134.
    Slesinger PA, Patil N, Liao YJ, Jan YN, Jan LY, Cox DR. Functional effects of the mouse weaver mutation on G protein-gated inwardly rectifying K+ channels. Neuron. 1996;16(2):321–31. PubMed PMID: 8789947.PubMedCrossRefGoogle Scholar
  135. 135.
    Furutama D, Morita N, Takano R, Sekine Y, Sadakata T, Shinoda Y, et al. Expression of the IP3R1 promoter-driven nls-lacZ transgene in Purkinje cell parasagittal arrays of developing mouse cerebellum. J Neurosci Res. 2010;88(13):2810–25. PubMed PMID: 20632399.PubMedGoogle Scholar
  136. 136.
    Bailey K, Rahimi Balaei M, Mehdizadeh M, Marzban H. Spatial and temporal expression of lysosomal acid phosphatase 2 (ACP2) reveals dynamic patterning of the mouse cerebellar cortex. Cerebellum. 2013;12(6):870–81. PubMed PMID: 23780826.PubMedCrossRefGoogle Scholar
  137. 137.
    Akintunde A, Eisenman LM. External cuneocerebellar projection and Purkinje cell zebrin II bands: a direct comparison of parasagittal banding in the mouse cerebellum. J Chem Neuroanat. 1994;7(1–2):75–86. PubMed PMID: 7802972.PubMedCrossRefGoogle Scholar
  138. 138.
    Ji Z, Hawkes R. Topography of Purkinje cell compartments and mossy fiber terminal fields in lobules II and III of the rat cerebellar cortex: spinocerebellar and cuneocerebellar projections. Neuroscience. 1994;61(4):935–54. PubMed PMID: 7530818.PubMedCrossRefGoogle Scholar
  139. 139.
    Dusart I, Guenet JL, Sotelo C. Purkinje cell death: differences between developmental cell death and neurodegenerative death in mutant mice. Cerebellum. 2006;5(2):163–73. PubMed PMID: 16818391. Epub 2006/07/05. eng.PubMedCrossRefGoogle Scholar
  140. 140.
    Jankowski J, Miething A, Schilling K, Baader SL. Physiological Purkinje cell death is spatiotemporally organized in the developing mouse cerebellum. Cerebellum. 2009;8(3):277–90. PubMed PMID: 19238501.PubMedCrossRefGoogle Scholar
  141. 141.
    Gillardon F, Baurle J, Wickert H, Grusser-Cornehls U, Zimmermann M. Differential regulation of bcl-2, bax, c-fos, junB, and krox-24 expression in the cerebellum of Purkinje cell degeneration mutant mice. J Neurosci Res. 1995;41(5):708–15. PubMed PMID: 7563251.PubMedCrossRefGoogle Scholar
  142. 142.
    Vogel MW. Cell death, Bcl-2, Bax, and the cerebellum. Cerebellum. 2002;1(4):277–87. PubMed PMID: 12879966PubMedCrossRefGoogle Scholar
  143. 143.
    Serra HG, Duvick L, Zu T, Carlson K, Stevens S, Jorgensen N, et al. RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell. 2006;127(4):697–708. PubMed PMID: 17110330.PubMedCrossRefGoogle Scholar
  144. 144.
    Basson MA, Wingate RJ. Congenital hypoplasia of the cerebellum: developmental causes and behavioral consequences. Front Neuroanat. 2013;7:29. PubMed PMID: 24027500. Pubmed Central PMCID: PMC3759752.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Tsai PT, Hull C, Chu Y, Greene-Colozzi E, Sadowski AR, Leech JM, et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature. 2012;488(7413):647–51. PubMed PMID: 22763451. Epub 2012/07/06. eng.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Zerbo O, Iosif AM, Walker C, Ozonoff S, Hansen RL, Hertz-Picciotto I. Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) study. J Autism Dev Disord. 2013;43(1):25–33. PubMed PMID: 22562209. Pubmed Central PMCID: PMC3484245.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Aavani T, Rana SA, Hawkes R, Pittman QJ. Maternal immune activation produces cerebellar hyperplasia and alterations in motor and social behaviors in male and female mice. Cerebellum. 2015;14(5):491–505. PubMed PMID: 25863812.PubMedCrossRefGoogle Scholar
  148. 148.
    Muguruma K, Nishiyama A, Ono Y, Miyawaki H, Mizuhara E, Hori S, et al. Ontogeny-recapitulating generation and tissue integration of ES cell-derived Purkinje cells. Nat Neurosci. 2010;13(10):1171–80. PubMed PMID: 20835252. Epub 2010/09/14. eng.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Università Vita-Salute San RaffaeleMilanItaly
  2. 2.Division of NeuroscienceSan Raffaele Scientific InstituteMilanItaly
  3. 3.Department of Cell Biology and Anatomy, and Hotchkiss Brain Institute, Cumming School of MedicineUniversity of CalgaryCalgaryCanada

Personalised recommendations