Abstract
The discovery by Altman and coworkers of adult-born microneurons in the olfactory bulb and dentate gyrus has triggered a long stream of studies and many attempts to harness adult neurogenesis, promote regeneration after injury, and contrast cognitive decline in the elderly. Likewise, the discovery of postnatal neurogenesis in the cerebellum has provided the framework for many subsequent molecular studies, including investigations of developmental processes and the assessment of GC progenitor (GCP) clonal expansion in the context of human disease. Here, I will briefly discuss some of the discoveries made in the field of cerebellar development over the years building upon the findings of Altman and his colleagues, touching upon signaling pathways that regulate granule cell neurogenesis and their involvement in developmental and neoplastic disorders of the cerebellum.
References
Consalez GG, Goldowitz D, Casoni F, Hawkes R. Origins, development, and compartmentation of the granule cells of the cerebellum. Front Neural Circuits. 2020;14: 611841. https://doi.org/10.3389/fncir.2020.611841.
Herculano-Houzel S, Mota B, Lent R. Cellular scaling rules for rodent brains. Proc Natl Acad Sci USA. 2006;103:12138–43. https://doi.org/10.1073/pnas.0604911103.
Ito M. The cerebellum and neural control. New York: Raven Press; 1984.
Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965;124:319–35. https://doi.org/10.1002/cne.901240303.
Altman J. Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol. 1969;137:433–57. https://doi.org/10.1002/cne.901370404.
Lledo PM, Alonso M, Grubb MS. Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci. 2006;7:179–93. https://doi.org/10.1038/nrn1867.
Deng W, Aimone JB, Gage FH. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci. 2010;11:339–50. https://doi.org/10.1038/nrn2822.
Das GD, Altman J. Postnatal neurogenesis in the cerebellum of the cat and tritiated thymidine autoradiography. Brain Res. 1971;30:323–30. https://doi.org/10.1016/0006-8993(71)90082-5.
Altman J. Postnatal development of the cerebellar cortex in the rat. I. The external germinal layer and the transitional molecular layer. J Comp Neurol. 1972;145:353–97. https://doi.org/10.1002/cne.901450305.
Saunders JW Jr. Death in embryonic systems. Science. 1966;154:604–12. https://doi.org/10.1126/science.154.3749.604.
Saunders JW Jr. The proximo-distal sequence of origin of the parts of the chick wing and the role of the ectoderm. J Exp Zool. 1948;108:363–403. https://doi.org/10.1002/jez.1401080304.
Le Lievre CS, Le Douarin NM. Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos. J Embryol Exp Morphol. 1975;34:125–54.
Le Douarin NM, Teillet MA. The migration of neural crest cells to the wall of the digestive tract in avian embryo. J Embryol Exp Morphol. 1973;30:31–48.
Chaplin N, Tendeng C, Wingate RJ. Absence of an external germinal layer in zebrafish and shark reveals a distinct, anamniote ground plan of cerebellum development. J Neurosci. 2010;30:3048–57. https://doi.org/10.1523/JNEUROSCI.6201-09.2010.
Haldipur P, Aldinger KA, Bernardo S, Deng M, Timms AE, Overman LM, Winter C, Lisgo SN, Razavi F, Silvestri E, Manganaro L, Adle-Biassette H, Guimiot F, Russo R, Kidron D, Hof PR, Gerrelli D, Lindsay SJ, Dobyns WB, Glass IA, Alexandre P, Millen KJ. Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum. Science. 2019;366:454–60. https://doi.org/10.1126/science.aax7526.
Choi Y, Borghesani PR, Chan JA, Segal RA. Migration from a mitogenic niche promotes cell-cycle exit. J Neurosci. 2005;25:10437–45. https://doi.org/10.1523/JNEUROSCI.1559-05.2005.
Nakashima K, Umeshima H, Kengaku M. Cerebellar granule cells are predominantly generated by terminal symmetric divisions of granule cell precursors. Dev Dyn. 2015;244:748–58. https://doi.org/10.1002/dvdy.24276.
Legué E, Riedel E, Joyner AL. Clonal analysis reveals granule cell behaviors and compartmentalization that determine the folded morphology of the cerebellum. Development. 2015;142:1661–71. https://doi.org/10.1242/dev.120287.
Smeyne RJ, Chu T, Lewin A, Bian F, Sanlioglu S, Kunsch C, Lira SA, Oberdick J. Local control of granule cell generation by cerebellar Purkinje cells. Mol Cell Neurosci. 1995;6:230–51. https://doi.org/10.1006/mcne.1995.1019.
Wechsler-Reya RJ, Scott MP. Control of neuronal precursor proliferation in the cerebellum by sonic hedgehog. Neuron. 1999;22:103–14.
Dahmane N, Ruiz-i-Altaba A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development. 1999;126:3089–100.
Wallace VA. Purkinje-cell-derived sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol. 1999;9:445–8.
Lewis PM, Gritli-Linde A, Smeyne R, Kottmann A, McMahon AP. Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum. Dev Biol. 2004;270:393–410. https://doi.org/10.1016/j.ydbio.2004.03.007.
Aguilar A, Meunier A, Strehl L, Martinovic J, Bonniere M, Attie-Bitach T, Encha-Razavi F, Spassky N. Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome. Proc Natl Acad Sci USA. 2012;109:16951–6. https://doi.org/10.1073/pnas.1201408109.
Haldipur P, Bharti U, Govindan S, Sarkar C, Iyengar S, Gressens P, Mani S. Expression of sonic hedgehog during cell proliferation in the human cerebellum. Stem Cells Dev. 2012;21:1059–68. https://doi.org/10.1089/scd.2011.0206.
Lee SJ, Lindsey S, Graves B, Yoo S, Olson JM, Langhans SA. Sonic hedgehog-induced histone deacetylase activation is required for cerebellar granule precursor hyperplasia in medulloblastoma. PLoS ONE. 2013;8: e71455. https://doi.org/10.1371/journal.pone.0071455.
Di Pietro C, Marazziti D, La Sala G, Abbaszadeh Z, Golini E, Matteoni R, Tocchini-Valentini GP. Primary cilia in the murine cerebellum and in mutant models of medulloblastoma. Cell Mol Neurobiol. 2017;37:145–54. https://doi.org/10.1007/s10571-016-0354-3.
Solecki DJ, Liu XL, Tomoda T, Fang Y, Hatten ME. Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron. 2001;31:557–68. https://doi.org/10.1016/s0896-6273(01)00395-6.
Anne SL, Govek EE, Ayrault O, Kim JH, Zhu X, Murphy DA, Van Aelst L, Roussel MF, Hatten ME. WNT3 inhibits cerebellar granule neuron progenitor proliferation and medulloblastoma formation via MAPK activation. PLoS ONE. 2013;8: e81769. https://doi.org/10.1371/journal.pone.0081769.
Kullmann JA, Trivedi N, Howell D, Laumonnerie C, Nguyen V, Banerjee SS, Stabley DR, Shirinifard A, Rowitch DH, Solecki DJ. Oxygen tension and the VHL-Hif1alpha pathway determine onset of neuronal polarization and cerebellar germinal zone exit. Neuron. 2020;106(607–23): e5. https://doi.org/10.1016/j.neuron.2020.02.025.
Grinberg I, Northrup H, Ardinger H, Prasad C, Dobyns WB, Millen KJ. Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation. Nat Genet. 2004;36:1053–5.
Aruga J, Millen KJ. ZIC1 Function in normal cerebellar development and human developmental pathology. Adv Exp Med Biol. 2018;1046:249–68. https://doi.org/10.1007/978-981-10-7311-3_13.
Aldinger KA, Lehmann OJ, Hudgins L, Chizhikov VV, Bassuk AG, Ades LC, Krantz ID, Dobyns WB, Millen KJ. FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nat Genet. 2009;41:1037–42. https://doi.org/10.1038/ng.422.
Romani M, Micalizzi A, Valente EM. Joubert syndrome: congenital cerebellar ataxia with the molar tooth. Lancet Neurol. 2013;12:894–905. https://doi.org/10.1016/S1474-4422(13)70136-4.
Parisi M and Glass I. Joubert syndrome. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 2003 (updated 2017).
Chang CH, Zanini M, Shirvani H, Cheng JS, Yu H, Feng CH, Mercier AL, Hung SY, Forget A, Wang CH, Cigna SM, Lu IL, Chen WY, Leboucher S, Wang WJ, Ruat M, Spassky N, Tsai JW, Ayrault O. Atoh1 controls primary cilia formation to allow for SHH-triggered granule neuron progenitor proliferation. Dev Cell. 2019;48(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, Yoder BK, Millen KJ. Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. J Neurosci. 2007;27:9780–9. https://doi.org/10.1523/JNEUROSCI.5586-06.2007.
Spassky N, Han YG, Aguilar A, Strehl L, Besse L, Laclef C, Ros MR, Garcia-Verdugo JM, Alvarez-Buylla A. Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool. Dev Biol. 2008;317:246–59. https://doi.org/10.1016/j.ydbio.2008.02.026.
Northcott PA, Robinson GW, Kratz CP, Mabbott DJ, Pomeroy SL, Clifford SC, Rutkowski S, Ellison DW, Malkin D, Taylor MD, Gajjar A, Pfister SM. Medulloblastoma Nat Rev Dis Primers. 2019;5:11. https://doi.org/10.1038/s41572-019-0063-6.
Merk DJ, Segal RA. Sonic hedgehog signaling is blue: insights from the patched mutant mice. Trends Neurosci. 2018;41:870–2. https://doi.org/10.1016/j.tins.2018.08.013.
Evans DG Farndon PA. Nevoid basal cell carcinoma syndrome. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 2002 (updated 2018).
Farioli-Vecchioli S, Cina I, Ceccarelli M, Micheli L, Leonardi L, Ciotti MT, De Bardi M, Di Rocco C, Pallini R, Cavallaro S, Tirone F. Tis21 knock-out enhances the frequency of medulloblastoma in Patched1 heterozygous mice by inhibiting the Cxcl3-dependent migration of cerebellar neurons. J Neurosci. 2012;32:15547–64. https://doi.org/10.1523/JNEUROSCI.0412-12.2012.
Lopes A, Magrinelli E and Telley L. Emerging roles of single-cell multi-omics in studying developmental temporal patterning. Int J Mol Sci 2020: 21. https://doi.org/10.3390/ijms21207491
Funding
This work was conducted without any funding from public or private sources.
Author information
Authors and Affiliations
Contributions
Concept, writing, and approval of the final version: GGC.
Corresponding author
Ethics declarations
Ethics Committee Approval
Not applicable.
Conflict of Interest
The author declares no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Appendix A
Appendix A
![figure a](http://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs12311-021-01315-x/MediaObjects/12311_2021_1315_Figa_HTML.png)
![figure b](http://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs12311-021-01315-x/MediaObjects/12311_2021_1315_Figb_HTML.png)
![figure c](http://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs12311-021-01315-x/MediaObjects/12311_2021_1315_Figc_HTML.png)
![figure d](http://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs12311-021-01315-x/MediaObjects/12311_2021_1315_Figd_HTML.png)
![figure e](http://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs12311-021-01315-x/MediaObjects/12311_2021_1315_Fige_HTML.png)
![figure f](http://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs12311-021-01315-x/MediaObjects/12311_2021_1315_Figf_HTML.png)
![figure g](http://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs12311-021-01315-x/MediaObjects/12311_2021_1315_Figg_HTML.png)
![figure h](http://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs12311-021-01315-x/MediaObjects/12311_2021_1315_Figh_HTML.png)
Rights and permissions
About this article
Cite this article
Consalez, G.G. The First 50 Years of Postnatal Neurogenesis in the Cerebellum: a Long Journey Across Phenomena, Mechanisms, and Human Disease. Cerebellum 21, 9–18 (2022). https://doi.org/10.1007/s12311-021-01315-x
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12311-021-01315-x