Key Points
-
The cerebellum represents 10% of the brain's total volume, but contains more than half of our neurons. It acts as a coordination centre, using sensory inputs from the periphery to fine-tune our movement and balance. It is one of the first structures in the brain to begin to differentiate, but one of the last to mature, and its cellular organization continues to change for many months after birth. The study of mouse homologues of Drosophila genes has provided valuable insights into the molecular basis of cerebellar development.
-
In humans, the cerebellum develops from the dorsal region of the posterior neural tube, and its cells arise from two germinal matrices. Most cells are derived from the ventricular zone, but the granule neurons come from a specialized germinal matrix called the rhombic lip.
-
The mesencephalon and metencephalon both contribute to the developing mouse cerebellum. The patterning of these two regions depends on signals from the isthmus organizer (IO), located just caudal to their junction. Otx2 and Gbx2 are central to IO development. Otx2 is expressed in the mesencephalon, with a posterior boundary at the rostral metencephalon; Gbx2 is expressed in the metencephalon, and its anterior boundary abuts the Otx2 boundary. Reciprocal repression maintains a sharp boundary between these domains. Otx2 and Gbx2 form part of a regulatory loop that includes Wnt1, En1 and Fgf8. Many other genes, including members of the Pax and Hox families, are also involved in patterning this region.
-
Purkinje cells (PCs), Golgi neurons, stellate and basket cells all arise from the ventricular neuroepithelium. PCs are born around embryonic day 13, and they migrate along radial glial fibres into the cerebellar anlage. During their final maturation phase, PCs develop extensive dendritic arbors and synapse onto granule neurons. This depends on granule neuron signals, probably including Wnt3. Various growth factors are required for PC survival, including nerve growth factor, acetylcholine, neurotrophin 4/5, brain-derived neurotrophic factor and ciliary neurotrophic factor.
-
The rhombic lip, located between the fourth ventricle and the metencephalic roof plate, gives rise to granule neurons. Proliferation in its germinal epithelium is governed by the Math1 gene. Rhombic lip cells migrate to the cerebellar anlage and settle on its periphery to form the external granule layer, another zone of proliferation. As the cells begin to migrate, they express markers that include RU49/Zipro1, Zic1 and Zic3. RU49/Zipro1 and Zic1 are thought to be involved in cell proliferation, which requires interaction with PCs. PCs might release a diffusible factor such as sonic hedgehog (Shh), and Zic1 could control cell proliferation by indirectly regulating the Shh pathway. The final stage of granule neuron maturation occurs after precursor cell migration into the inner granule layer.
-
Many genes, including En1, En2, Pax2, Wnt7b, and some of the ephrins and their receptors, show characteristic patterns of spatial expression in the cerebellum, but only En2 has been studied specifically for its role in compartmentalization. In addition to the patterning genes, several other gene families, such as the heat shock proteins and proteins involved in neuronal migration, are also expressed in specific patterns. Spatial- and temporal-specific knockout strategies should yield more information about the roles of these genes in patterning the cerebellum.
Abstract
The cerebellum is one of the first brain structures to begin to differentiate, yet it is one of the last to achieve maturity — the cellular organization of the cerebellum continues to change for many months after birth. This protracted developmental process creates a special susceptibility to disruptions during embryogenesis and makes the cerebellum highly amenable to study. Over the past few years, genetic research has provided a great deal of information about the molecular events directing the formation of the cerebellum. Knowledge of these mechanisms should enable us to address the nature of human diseases that have their root in developmental processes.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Voogd, J. & Glickstein, M. The anatomy of the cerebellum. Trends Neurosci. 21, 370–375 (1998).
Middleton, F. A. & Strick, P. L. The cerebellum: an overview. Trends Neurosci. 21, 367–369 (1998).
Hatten, M. E. & Heintz, N. Mechanisms of neural patterning and specification in the developing cerebellum. Annu. Rev. Neurosci. 18, 385–408 (1995).
Hallonet, M. E., Teillet, M. A. & Le Douarin, N. M. A new approach to the development of the cerebellum provided by the quail–chick marker system. Development 108, 19–31 (1990).Describes the lineage analysis experiments that revealed the dual origin of the cerebellum from the mesencephalon and metencephalon.
Hallonet, M. E. & Le Douarin, N. M. Tracing neuroepithelial cells of the mesencephalic and metencephalic alar plates during cerebellar ontogeny in quail–chick chimaeras. Eur. J. Neurosci. 5, 1145–1155 (1993).
Simeone, A. Positioning the isthmic organizer where Otx2 and Gbx2 meet. Trends Genet. 16, 237–240 (2000).
Ang, S. L. et al. A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. Development 122, 243–252 (1996).
Wassarman, K. M. et al. Specification of the anterior hindbrain and establishment of a normal mid/hindbrain organizer is dependent on Gbx2 gene function. Development 124, 2923–2934 (1997).
Broccoli, V., Boncinelli, E. & Wurst, W. The caudal limit of Otx2 expression positions the isthmic organizer. Nature 401, 164–168 (1999).
Millet, S. et al. A role for Gbx2 in repression of Otx2 and positioning the mid/hindbrain organizer. Nature 401, 161–164 (1999).The two articles above describe the establishment of the isthmus organizer through the interaction between Gbx2 and Otx2.
Wurst, W. & Bally-Cuif, L. Neural plate patterning: upstream and downstream of the isthmus organizer. Nature Rev. Neurosci. 2, 99–108 (2001).This is one of the most thorough recent reviews on mid-/hindbrain patterning.
Joyner, A., Liu, A. & Millet, S. Otx2, Gbx2, Fgf8 interact to position and maintain a mid–hindbrain organizer. Curr. Opin. Cell Biol. 12, 736–741 (2000).
Rhinn, M. & Brand, M. The midbrain–hindbrain boundary organizer. Curr. Opin. Neurobiol. 11, 34–42 (2001).
Martinez, S., Crossley, P. H., Cobos, I., Rubenstein, J. L. & Martin, G. R. FGF8 induces formation of an ectopic isthmic organizer and isthmocerebellar development via a repressive effect on Otx2 expression. Development 126, 1189–1200 (1999).
Meyers, E. N., Lewandoski, M. & Martin, G. R. An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nature Genet. 18, 136–141 (1998).
Reifers, F. et al. Fgf8 is mutated in zebrafish acerebellar (ace) mutants and is required for maintenance of midbrain–hindbrain boundary development and somitogenesis. Development 125, 2381–2395 (1998).
Adams, K. A., Maida, J. M., Golden, J. A. & Riddle, R. D. The transcription factor Lmx1b maintains Wnt1 expression within the isthmic organizer. Development 127, 1857–1867 (2000).
McMahon, A. P., Joyner, A. L., Bradley, A. & McMahon, J. A. The midbrain–hindbrain phenotype of Wnt-1-/Wnt-1- mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum. Cell 69, 581–595 (1992).
McMahon, A. P. & Bradley, A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 62, 1073–1085 (1990).
Wurst, W., Auerbach, A. B. & Joyner, A. L. Multiple developmental defects in Engrailed-1 mutant mice: an early mid-hindbrain deletion and patterning defects in forelimbs and sternum. Development 120, 2065–2075 (1994).
Joyner, A. L. Engrailed, Wnt and Pax genes regulate midbrain–hindbrain development. Trends Genet. 12, 15–20 (1996).
Favor, J. et al. The mouse Pax21Neu mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney. Proc. Natl Acad. Sci. USA 93, 13870–13875 (1996).
Urbanek, P., Fetka, I., Meisler, M. H. & Busslinger, M. Cooperation of Pax2 and Pax5 in midbrain and cerebellum development. Proc. Natl Acad. Sci. USA 94, 5703–5708 (1997).
Gavalas, A., Davenne, M., Lumsden, A., Chambon, P. & Rijli, F. M. Role of Hoxa-2 in axon pathfinding and rostral hindbrain patterning. Development 124, 3693–3702 (1997).
Alder, J., Lee, K. J., Jessell, T. M. & Hatten, M. E. Generation of cerebellar granule neurons in vivo by transplantation of BMP-treated neural progenitor cells. Nature Neurosci. 2, 535–540 (1999).
Zhang, X. M., Lin, E. & Yang, X. J. Sonic hedgehog-mediated ventralization disrupts formation of the midbrain–hindbrain junction in the chick embryo. Dev. Neurosci. 22, 207–216 (2000).
Hatten, M. E. Central nervous system neuronal migration. Annu. Rev. Neurosci. 22, 511–539 (1999).This review synthesizes recent advances in our understanding of neuronal migration.
Miyata, T., Nakajima, K., Mikoshiba, K. & Ogawa, M. Regulation of Purkinje cell alignment by Reelin as revealed with CR-50 antibody. J. Neurosci. 17, 3599–3609 (1997).
Rice, D. S. & Curran, T. Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS. Genes Dev. 13, 2758–2773 (1999).
Rakic, P. & Sidman, R. L. Organization of cerebellar cortex secondary to deficit of granule cells in weaver mutant mice. J. Comp. Neurol. 152, 133–161 (1973).
Ben-Arie, N. et al. Math1 is essential for genesis of cerebellar granule neurons. Nature 390, 169–172 (1997).Describes the role of Math1 in the development of the rhombic lip and the genesis of granule neurons.
Kakizawa, S., Yamasaki, M., Watanabe, M. & Kano, M. Critical period for activity-dependent synapse elimination in developing cerebellum. J. Neurosci. 20, 4954–4961 (2000).
Goldowitz, D. & Hamre, K. The cells and molecules that make a cerebellum. Trends Neurosci. 21, 375–382 (1998).
Baptista, C. A., Hatten, M. E., Blazeski, R. & Mason, C. A. Cell–cell interactions influence survival and differentiation of purified Purkinje cells in vitro. Neuron 12, 243–260 (1994).
Salinas, P. C., Fletcher, C., Copeland, N. G., Jenkins, N. A. & Nusse, R. Maintenance of Wnt-3 expression in Purkinje cells of the mouse cerebellum depends on interactions with granule cells. Development 120, 1277–1286 (1994).
Mount, H. T., Dreyfus, C. F. & Black, I. B. Muscarinic stimulation promotes cultured Purkinje cell survival: a role for acetylcholine in cerebellar development? J. Neurochem. 63, 2065–2073 (1994).
Larkfors, L., Lindsay, R. M. & Alderson, R. F. Characterization of the responses of Purkinje cells to neurotrophin treatment. J. Neurochem. 66, 1362–1373 (1996).
Vogel, M. W., Sinclair, M., Qiu, D. & Fan, H. Purkinje cell fate in staggerer mutants: agenesis versus cell death. J. Neurobiol. 42, 323–337 (2000).
Zanjani, H. S., Vogel, M. W., Delhaye-Bouchaud, N., Martinou, J. C. & Mariani, J. Increased cerebellar Purkinje cell numbers in mice overexpressing a human bcl-2 transgene. J. Comp. Neurol. 374, 332–341 (1996).
Wingate, R. J. The rhombic lip and early cerebellar development. Curr. Opin. Neurobiol. 11, 82–88 (2001).
Wingate, R. J. & Hatten, M. E. The role of the rhombic lip in avian cerebellum development. Development 126, 4395–4404 (1999).Describes lineages and migration of rhombic lip cells.
Ben-Arie, N. et al. Evolutionary conservation of sequence and expression of the bHLH protein Atonal suggests a conserved role in neurogenesis. Hum. Mol. Genet. 5, 1207–1216 (1996).
Ben-Arie, N. et al. Functional conservation of atonal and Math1 in the CNS and PNS. Development 127, 1039–1048 (2000).
Alder, J., Cho, N. K. & Hatten, M. E. Embryonic precursor cells from the rhombic lip are specified to a cerebellar granule neuron identity. Neuron 17, 389–399 (1996).
Yang, X. W., Zhong, R. & Heintz, N. Granule cell specification in the developing mouse brain as defined by expression of the zinc finger transcription factor RU49. Development 122, 555–566 (1996).
Yang, X. W., Wynder, C., Doughty, M. L. & Heintz, N. BAC-mediated gene-dosage analysis reveals a role for Zipro1 (Ru49/Zfp38) in progenitor cell proliferation in cerebellum and skin. Nature Genet. 22, 327–335 (1999).
Aruga, J. et al. Mouse Zic1 is involved in cerebellar development. J. Neurosci. 18, 284–293 (1998).
Brown, S. A. et al. Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nature Genet. 20, 180–183 (1998).
Gebbia, M. et al. X-linked situs abnormalities result from mutations in ZIC3. Nature Genet. 17, 305–308 (1997).
Gao, W. O., Heintz, N. & Hatten, M. E. Cerebellar granule cell neurogenesis is regulated by cell–cell interactions in vitro. Neuron 6, 705–715 (1991).
Dahmane, N. & Ruiz-i-Altaba, A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126, 3089–3100 (1999).
Wechsler-Reya, R. J. & Scott, M. P. Control of neuronal precursor proliferation in the cerebellum by Sonic hedgehog. Neuron 22, 103–114 (1999).
Wechsler-Reya, R. & Scott, M. P. The developmental biology of brain tumors. Annu. Rev. Neurosci. 24, 385–428 (2001).
Mizugishi, K., Aruga, J., Nakata, K. & Mikoshiba, K. Molecular properties of Zic proteins as transcriptional regulators and their relationship to GLI proteins. J. Biol. Chem. 276, 2180–2188 (2001).
Huard, J. M., Forster, C. C., Carter, M. L., Sicinski, P. & Ross, M. E. Cerebellar histogenesis is disturbed in mice lacking cyclin D2. Development 126, 1927–1935 (1999).
Engelkamp, D., Rashbass, P., Seawright, A. & Van Heyningen, V. Role of Pax6 in development of the cerebellar system. Development 126, 3585–3596 (1999).
Miyazawa, K. et al. A role for p27/Kip1 in the control of cerebellar granule cell precursor proliferation. J. Neurosci. 20, 5756–5763 (2000).
Miyata, T., Maeda, T. & Lee, J. E. NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. Genes Dev. 13, 1647–1652 (1999).
Duncan, M. K., Bordas, L., Dicicco-Bloom, E. & Chada, K. K. Expression of the helix–loop–helix genes Id-1 and NSCL-1 during cerebellar development. Dev. Dyn. 208, 107–114 (1997).
Li, C. M., Yan, R. T. & Wang, S. Z. Misexpression of a bHLH gene, cNSCL1, results in abnormal brain development. Dev. Dyn. 215, 238–247 (1999).
Tomoda, T., Bhatt, R. S., Kuroyanagi, H., Shirasawa, T. & Hatten, M. E. A mouse serine/threonine kinase homologous to C. elegans UNC51 functions in parallel fiber formation of cerebellar granule neurons. Neuron 24, 833–846 (1999).
Zheng, C., Heintz, N. & Hatten, M. E. CNS gene encoding astrotactin, which supports neuronal migration along glial fibers. Science 272, 417–419 (1996).
Adams, J. C. & Tucker, R. P. The thrombospondin type 1 repeat (TSR) superfamily: diverse proteins with related roles in neuronal development. Dev. Dyn. 218, 280–299 (2000).
Husmann, K., Faissner, A. & Schachner, M. Tenascin promotes cerebellar granule cell migration and neurite outgrowth by different domains in the fibronectin type III repeats. J. Cell Biol. 116, 1475–1486 (1992).
Raetzman, L. T. & Siegel, R. E. Immature granule neurons from cerebella of different ages exhibit distinct developmental potentials. J. Neurobiol. 38, 559–570 (1999).
Hall, A. C., Lucas, F. R. & Salinas, P. C. Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell 100, 525–535 (2000).
Berglund, E. O. et al. Ataxia and abnormal cerebellar microorganization in mice with ablated contactin gene expression. Neuron 24, 739–750 (1999).
Rodriguez, C. I. & Dymecki, S. M. Origin of the precerebellar system. Neuron 27, 475–486 (2000).
Lin, J. C., Cai, L. & Cepko C. L. The external granule layer of the developing chick cerebellum generates granule cells and cells of the isthmus and rostral hindbrain. J. Neurosci. 21, 159–168 (2001).
Herrup, K. & Kuemerle, B. The compartmentalization of the cerebellum. Annu. Rev. Neurosci. 20, 61–90 (1997).
Millen, K. J., Hui, C. C. & Joyner, A. L. A role for En-2 and other murine homologues of Drosophila segment polarity genes in regulating positional information in the developing cerebellum. Development 121, 3935–3945 (1995).
Karam, S. D. et al. Eph receptors and ephrins in the developing chick cerebellum: relationship to sagittal patterning and granule cell migration. J. Neurosci. 20, 6488–6500 (2000).
Millen, K. J., Wurst, W., Herrup, K. & Joyner, A. L. Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse Engrailed-2 mutants. Development 120, 695–706 (1994).
Baader, S. L., Vogel, M. W., 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. 19, 5370–5379 (1999).
Armstrong, C. L., Krueger-Naug, A. M., Currie, R. W. & Hawkes, R. Expression of heat-shock protein Hsp25 in mouse Purkinje cells during development reveals novel features of cerebellar compartmentation. J. Comp. Neurol. 429, 7–21 (2001).
Lin, J. C. & Cepko, C. L. Granule cell raphes and parasagittal domains of Purkinje cells: complementary patterns in the developing chick cerebellum. J. Neurosci. 18, 9342–9353 (1998).
Lin J. C. & Cepko, C. L. Biphasic dispersion of clones containing Purkinje cells and glia in the developing chick cerebellum. Dev. Biol. 211, 177–197 (1999).
Hawkes, R. & Turner, R. W. Compartmentation of NADPH-diaphorase activity in the anterior lobe vermis of the mouse cerebellar cortex. Proc. West. Pharmacol. Soc. 37, 35–38 (1994).
Oberdick, J., Baader, S. L. & Schilling, K. From zebra stripes to postal zones: deciphering patterns of gene expression in the cerebellum. Trends Neurosci. 21, 383–390 (1998).This review discusses various hypotheses on cerebellar compartmentalization.
Acknowledgements
The authors would like to thank V. Brandt for her input; H.Y.Z. is a Howard Hughes Medical Institute Investigator; V.Y.W. is supported by a pre-doctoral NRSA fellowship and is a McNair Scholar.
Author information
Authors and Affiliations
Related links
Related links
DATABASE LINKS
Glossary
- GOLGI INTERNEURONS
-
Cerebellar interneurons located in the granule cell layer. Their axonal terminals form part of the cerebellar glomeruli.
- STELLATE INTERNEURONS
-
Cerebellar interneurons located in the molecular layer that project to Purkinje cells.
- BASKET CELLS
-
Interneurons that send their axons to the cell body of the postsynaptic cell, surrounding it with a structure akin to a basket.
- CHIARI MALFORMATION
-
Downward displacement of the cerebellum and brainstem; the spinal cord might also be deformed.
- DANDI–WALKER MALFORMATION
-
Cystic transformation of the fourth ventricle.
- PARALLEL FIBRES
-
The axons of cerebellar granule cells. Parallel fibres emerge from the molecular layer of the cerebellar cortex towards the periphery, where they extend branches perpendicular to the main axis of the Purkinje neurons and form the so-called en passant synapses with this cell type.
- CLIMBING FIBRES
-
Cerebellar afferents that arise from the inferior olivary nucleus, each of which forms multiple synapses with a single Purkinje cell.
- CHICK–QUAIL CHIMAERA
-
A chick that has received a piece of quail tissue as a transplant; the derivative of the transplanted tissue allows fate-mapping analysis.
- ISTHMUS
-
A narrow section of the brainstem, which separates the midbrain from the pons.
- ROOF PLATE
-
The point of fusion of the neural folds, forming the dorsal-most part of the neural tube.
- FOLIA
-
The characteristic folds of the cerebellar surface.
- SITUS INVERSUS
-
A syndrome in which the position of the internal organs is reversed.
- BASAL CELL NAEVUS SYNDROME
-
Causes basal cell carcinoma and, in 10% of cases, medulloblastoma.
- DOMINANT-NEGATIVE
-
A mutant molecule capable of forming a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.
- MOSSY FIBRES
-
Cerebellar afferents that constitute the main input to the granule cells. They also project to the deep cerebellar nuclei.
Rights and permissions
About this article
Cite this article
Wang, V., Zoghbi, H. Genetic regulation of cerebellar development. Nat Rev Neurosci 2, 484–491 (2001). https://doi.org/10.1038/35081558
Issue Date:
DOI: https://doi.org/10.1038/35081558
This article is cited by
-
Population-wide cerebellar growth models of children and adolescents
Nature Communications (2024)
-
Disruption of protein geranylgeranylation in the cerebellum causes cerebellar hypoplasia and ataxia via blocking granule cell progenitor proliferation
Molecular Brain (2023)
-
Altered cerebellar lobular volumes correlate with clinical deficits in siblings and children with ASD: evidence from toddlers
Journal of Translational Medicine (2023)
-
Single-cell epigenomics and spatiotemporal transcriptomics reveal human cerebellar development
Nature Communications (2023)
-
Uncovering the genetic profiles underlying the intrinsic organization of the human cerebellum
Molecular Psychiatry (2022)