Abstract
The mechanisms of cerebellar neurogenesis have been redefined in the last few years, showing the precise spatiotemporal sequence of neuronal generation from neurochemically heterogeneous pools of progenitors. Here we describe these processes, highlighting the principal strategies used within this system to generate appropriate cell numbers and phenotypes.
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References
Aguado C, Fernandez-Alacid L, Cabanero MJ, Yanagawa Y, Schilling K, Watanabe M et al (2013) Differential maturation of GIRK2-expressing neurons in the mouse cerebellum. J Chem Neuroanat 47:79–89. https://doi.org/10.1016/j.jchemneu.2012.11.001
Aguilar A, Meunier A, Strehl L, Martinovic J, Bonniere M, Attie-Bitach T et al (2012) Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome. Proc Natl Acad Sci U S A 109(42):16951–16956. https://doi.org/10.1073/pnas.1201408109
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(15):8730–8738. https://doi.org/10.1074/jbc.270.15.8730
Alder J, Cho NK, Hatten ME (1996) Embryonic precursor cells from the rhombic lip are specified to a cerebellar granule neuron identity. Neuron 17(3):389–399
Altman J (1972) Postnatal development of the cerebellar cortex in the rat. III. Maturation of the components of the granular layer. J Comp Neurol 145(4):465–513. https://doi.org/10.1002/cne.901450403
Altman J, Bayer SA (1997) Development of the cerebellar system in relation to its evolution, structure, and functions. CRC Press, Boca Raton
Ben-Arie N, McCall A, Berkman S, Eichele G, Bellen H, Zoghbi H (1996) Evolutionary conservation of sequence and expression of the bHLH protein atonal suggests a conserved role in neurogenesis. Hum Mol Genet 5:1207–1216
Broccoli V, Boncinelli E, Wurst W (1999) The caudal limit of Otx2 expression positions the isthmic organizer. Nature 401(6749):164–168
Carletti B, Rossi F (2008) Neurogenesis in the cerebellum. Neuroscientist 14(1):91–100. https://doi.org/10.1177/1073858407304629
Casoni F, Croci L, Bosone C, D'Ambrosio R, Badaloni A, Gaudesi D et al (2017) Zfp423/ZNF423 regulates cell cycle progression, the mode of cell division and the DNA-damage response in Purkinje neuron progenitors. Development 144(20):3686–3697. https://doi.org/10.1242/dev.155077
Casoni F, Croci L, Vincenti F, Podini P, Riba M, Massimino L et al (2020) ZFP423 regulates early patterning and multiciliogenesis in the hindbrain choroid plexus. Development 147(22):190173. https://doi.org/10.1242/dev.190173
Chang CH, Zanini M, Shirvani H, Cheng JS, Yu H, Feng CH et al (2019) Atoh1 controls primary cilia formation to allow for SHH-triggered granule neuron progenitor proliferation. Dev Cell 48(2):184–99 e5. https://doi.org/10.1016/j.devcel.2018.12.017
Chizhikov VV, Davenport J, Zhang Q, Shih EK, Cabello OA, Fuchs JL et al (2007) Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. J Neurosci 27(36):9780–9789. https://doi.org/10.1523/JNEUROSCI.5586-06.2007
Chung S-H, Marzban H, Croci L, Consalez G, Hawkes R (2008) Purkinje cell subtype specification in the cerebellar cortex: Ebf2 acts to repress the Zebrin II-positive Purkinje cell phenotype. Neuroscience 153:721–732
Consalez GG, Hawkes R (2013) The compartmental restriction of cerebellar interneurons. Front Neural Circuits 6:123. https://doi.org/10.3389/fncir.2012.00123
Consalez GG, Goldowitz D, Casoni F, Hawkes R (2020) Origins, development, and compartmentation of the granule cells of the cerebellum. Front Neural Circuits 14:611841. https://doi.org/10.3389/fncir.2020.611841
Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF (2005) Vertebrate smoothened functions at the primary cilium. Nature 437(7061):1018–1021. https://doi.org/10.1038/nature04117
Croci L, Chung SH, Masserdotti G, Gianola S, Bizzoca A, Gennarini G et al (2006) A key role for the HLH transcription factor EBF2COE2,O/E-3 in Purkinje neuron migration and cerebellar cortical topography. Development 133(14):2719–2729. https://doi.org/10.1242/dev.02437
Croci L, Barili V, Chia D, Massimino L, van Vugt R, Masserdotti G et al (2011) Local insulin-like growth factor I expression is essential for Purkinje neuron survival at birth. Cell Death Differ 18(1):48–59. https://doi.org/10.1038/cdd.2010.78
Dahmane N, Ruiz-i-Altaba A (1999) Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126(14):3089–3100
Englund C, Kowalczyk T, Daza RA, Dagan A, Lau C, Rose MF et al (2006) Unipolar brush cells of the cerebellum are produced in the rhombic lip and migrate through developing white matter. J Neurosci 26(36):9184–9195
Fink AJ, Englund C, Daza RA, Pham D, Lau C, Nivison M et al (2006) Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip. J Neurosci 26(11):3066–3076. https://doi.org/10.1523/JNEUROSCI.5203-05.2006
Fleming JT, He W, Hao C, Ketova T, Pan FC, Wright CC et al (2013) The Purkinje neuron acts as a central regulator of spatially and functionally distinct cerebellar precursors. Dev Cell 27(3):278–292. https://doi.org/10.1016/j.devcel.2013.10.008
Florio M, Leto K, Muzio L, Tinterri A, Badaloni A, Croci L et al (2012) Neurogenin 2 regulates progenitor cell-cycle progression and Purkinje cell dendritogenesis in cerebellar development. Development 139(13):2308–2320. https://doi.org/10.1242/dev.075861
Fujita S, Shimada M, Nakamura T (1966) H3-Thymidine autoradiographic studies on the cell proliferation and differentiation in the external and the internal granular layers of the mouse cerebellum. J Comp Neurol 128(2):191–208. https://doi.org/10.1002/cne.901280206
Gao WQ, Hatten ME (1994) Immortalizing oncogenes subvert the establishment of granule cell identity in developing cerebellum. Development 120(5):1059–1070
Hallonet M, Alvarado-Mallart RM (1997) The chick/quail chimeric system: a model for early cerebellar development. Perspect Dev Neurobiol 5(1):17–31
Hallonet ME, Le Douarin NM (1993) Tracing neuroepithelial cells of the mesencephalic and metencephalic alar plates during cerebellar ontogeny in quail-chick chimaeras. Eur J Neurosci 5(9):1145–1155
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(1):19–31
Hatten ME, Heintz N (1995) Mechanisms of neural patterning and specification in the developing cerebellum. Ann Rev Neurosci 18:385–408
Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK (2005) Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 1(4):e53. https://doi.org/10.1371/journal.pgen.0010053
Helms AW, Johnson JE (1998) Progenitors of dorsal commissural interneurons are defined by MATH1 expression. Development 125(5):919–928
Henke RM, Savage TK, Meredith DM, Glasgow SM, Hori K, Dumas J et al (2009) Neurog2 is a direct downstream target of the Ptf1a-Rbpj transcription complex in dorsal spinal cord. Development 136(17):2945–2954. https://doi.org/10.1242/dev.035352
Hong CJ, Hamilton BA (2016) Zfp423 regulates sonic hedgehog signaling via primary cilium function. PLoS Genet 12(10):e1006357. https://doi.org/10.1371/journal.pgen.1006357
Hoshino M (2012) Neuronal subtype specification in the cerebellum and dorsal hindbrain. Dev Growth Differ 54(3):317–326. https://doi.org/10.1111/j.1440-169X.2012.01330.x
Hoshino M, Nakamura S, Mori K, Kawauchi T, Terao M, Nishimura YV et al (2005) Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron 47(2):201–213. https://doi.org/10.1016/j.neuron.2005.06.007
Huang X, Liu J, Ketova T, Fleming JT, Grover VK, Cooper MK et al (2010) Transventricular delivery of sonic hedgehog is essential to cerebellar ventricular zone development. Proc Natl Acad Sci U S A 107(18):8422–8427. https://doi.org/10.1073/pnas.0911838107
Huangfu D, Anderson KV (2005) Cilia and hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A 102(32):11325–11330. https://doi.org/10.1073/pnas.0505328102
Ito M (1984) The cerebellum and neural control. Raven Press, Madison
Komuro H, Yacubova E, Yacubova E, Rakic P (2001) Mode and tempo of tangential cell migration in the cerebellar external granular layer. J Neurosci 21(2):527–540
Kullmann JA, Trivedi N, Howell D, Laumonnerie C, Nguyen V, Banerjee SS et al (2020) Oxygen tension and the VHL-Hif1alpha pathway determine onset of neuronal polarization and cerebellar germinal zone exit. Neuron 106(4):607–23 e5. https://doi.org/10.1016/j.neuron.2020.02.025
Larouche M, Hawkes R (2006) From clusters to stripes: the developmental origins of adult cerebellar compartmentation. Cerebellum 5(2):77–88. https://doi.org/10.1080/14734220600804668
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(45):11682–11694. https://doi.org/10.1523/JNEUROSCI.3656-06.2006
Leto K, Bartolini A, Yanagawa Y, Obata K, Magrassi L, Schilling K et al (2009) Laminar fate and phenotype specification of cerebellar GABAergic interneurons. J Neurosci 29(21):7079–7091. https://doi.org/10.1523/JNEUROSCI.0957-09.2009
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(2):393–410. https://doi.org/10.1016/j.ydbio.2004.03.007
Li JY, Lao Z, Joyner AL (2005) New regulatory interactions and cellular responses in the isthmic organizer region revealed by altering Gbx2 expression. Development 132(8):1971–1981. https://doi.org/10.1242/dev.01727
Lin JC, Cai L, Cepko CL (2001) The external granule layer of the developing chick cerebellum generates granule cells and cells of the isthmus and rostral hindbrain. J Neurosci 21(1):159–168
Liu A, Wang B, Niswander LA (2005) Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development 132(13):3103–3111. https://doi.org/10.1242/dev.01894
Machold R, Fishell G (2005) Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron 48(1):17–24. https://doi.org/10.1016/j.neuron.2005.08.028
Machold RP, Kittell DJ, Fishell GJ (2007) Antagonism between notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip. Neural Dev 2:5
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(2):281–294. https://doi.org/10.1002/(sici)1097-4695(19991105)41:2<281::aid-neu10>3.0.co;2-5
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 en. Neuron 6(6):971–981
Martinez S, Crossley PH, Cobos I, Rubenstein JL, Martin GR (1999) FGF8 induces formation of an ectopic isthmic organizer and isthmocerebellar development via a repressive effect on Otx2 expression. Development 126(6):1189–1200
May SR, Ashique AM, Karlen M, Wang B, Shen Y, Zarbalis K et al (2005) Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol 287(2):378–389. https://doi.org/10.1016/j.ydbio.2005.08.050
Miale IL, Sidman RL (1961) An autoradiographic analysis of histogenesis in the mouse cerebellum. Exp Neurol 4:277–296. https://doi.org/10.1016/0014-4886(61)90055-3
Morales D, Hatten ME (2006) Molecular markers of neuronal progenitors in the embryonic cerebellar anlage. J Neurosci 26(47):12226–12236. https://doi.org/10.1523/JNEUROSCI.3493-06.2006
Mullen RJ, Eicher EM, Sidman RL (1976) Purkinje cell degeneration, a new neurological mutation in the mouse. Proc Natl Acad Sci U S A 73(1):208–212. https://doi.org/10.1073/pnas.73.1.208
Napieralski JA, Eisenman LM (1993) Developmental analysis of the external granular layer in the meander tail mutant mouse: do cerebellar microneurons have independent progenitors? Dev Dyn 197(4):244–254. https://doi.org/10.1002/aja.1001970403
Nunzi MG, Birnstiel S, Bhattacharyya BJ, Slater NT, Mugnaini E (2001) Unipolar brush cells form a glutamatergic projection system within the mouse cerebellar cortex. J Comp Neurol 434(3):329–341
Palay SL, Chan-Palay V (1974) Cerebellar cortex: cytology and organization. Springer, Berlin
Rakic P (1990) Principles of neural cell migration. Experientia 46(9):882–891. https://doi.org/10.1007/BF01939380
Ramón y Cajal S (1911) Histologie du système nerveux de l’homme et des vertébrés. Maloine, Paris
Sekerkova G, Ilijic E, Mugnaini E (2004) Time of origin of unipolar brush cells in the rat cerebellum as observed by prenatal bromodeoxyuridine labeling. Neuroscience 127(4):845–858. https://doi.org/10.1016/j.neuroscience.2004.05.050
Seto Y, Nakatani T, Masuyama N, Taya S, Kumai M, Minaki Y et al (2014) Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum. Nat Commun 5:3337. https://doi.org/10.1038/ncomms4337
Silbereis J, Heintz T, Taylor MM, Ganat Y, Ment LR, Bordey A et al (2010) Astroglial cells in the external granular layer are precursors of cerebellar granule neurons in neonates. Mol Cell Neurosci 44(4):362–373. https://doi.org/10.1016/j.mcn.2010.05.001
Smeyne RJ, Chu T, Lewin A, Bian F, Salih S, Kunsch C et al (1995) Local control of granule cell generation by cerebellar Purkinje cells. Mol Cell Neurosci 6(3):230–251
Sonmez E, Herrup K (1984) Role of staggerer gene in determining cell number in cerebellar cortex. II. Granule cell death and persistence of the external granule cell layer in young mouse chimeras. Brain Res 314(2):271–283. https://doi.org/10.1016/0165-3806(84)90049-x
Sotelo C (2004) Cellular and genetic regulation of the development of the cerebellar system. Prog Neurobiol 72(5):295–339
Spassky N, Han YG, Aguilar A, Strehl L, Besse L, Laclef C et al (2008) Primary cilia are required for cerebellar development and SHH-dependent expansion of progenitor pool. Dev Biol 317(1):246–259. https://doi.org/10.1016/j.ydbio.2008.02.026
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(30):11055–11069. https://doi.org/10.1523/JNEUROSCI.0479-11.2011
Valente EM, Silhavy JL, Brancati F, Barrano G, Krishnaswami SR, Castori M et al (2006) Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet 38(6):623–625. https://doi.org/10.1038/ng1805
Vogel MW, Sunter K, Herrup K (1989) Numerical matching between granule and Purkinje cells in lurcher chimeric mice: a hypothesis for the trophic rescue of granule cells from target-related cell death. J Neurosci 9(10):3454–3462
Wallace VA (1999) Purkinje-cell-derived sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol 9:445–448
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(1):31–43. https://doi.org/10.1016/j.neuron.2005.08.024
Wechsler-Reya RJ, Scott MP (1999) Control of neuronal precursor proliferation in the cerebellum by sonic hedgehog. Neuron 22(1):103–114
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(2):466–478. https://doi.org/10.1111/j.1460-9568.2006.04915.x
Wingate RJ (2001) The rhombic lip and early cerebellar development. Curr Opin Neurobiol 11(1):82–88. https://doi.org/10.1016/S0959-4388(00)00177-X
Wingate RJ, Hatten ME (1999) The role of the rhombic lip in avian cerebellum development. Development 126(20):4395–4404
Yamada M, Seto Y, Taya S, Owa T, Inoue YU, Inoue T et al (2014) Specification of spatial identities of cerebellar neuron progenitors by ptf1a and atoh1 for proper production of GABAergic and glutamatergic neurons. J Neurosci 34(14):4786–4800. https://doi.org/10.1523/JNEUROSCI.2722-13.2014
Zhang L, Goldman JE (1996a) Developmental fates and migratory pathways of dividing progenitors in the postnatal rat cerebellum. J Comp Neurol 370(4):536–550
Zhang L, Goldman JE (1996b) Generation of cerebellar interneurons from dividing progenitors in white matter. Neuron 16(1):47–54. https://doi.org/10.1016/s0896-6273(00)80022-7
Zordan P, Croci L, Hawkes R, Consalez GG (2008) Comparative analysis of proneural gene expression in the embryonic cerebellum. Dev Dyn 237(6):1726–1735. https://doi.org/10.1002/dvdy.21571
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We thank Ketty Leto for her past contribution to this work.
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Hawkes, R., Consalez, G.G. (2023). Cerebellar Neurogenesis. In: Gruol, D.L., Koibuchi, N., Manto, M., Molinari, M., Schmahmann, J.D., Shen, Y. (eds) Essentials of Cerebellum and Cerebellar Disorders. Springer, Cham. https://doi.org/10.1007/978-3-031-15070-8_13
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