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Specification of the Cerebellar Territory

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Handbook of the Cerebellum and Cerebellar Disorders

Abstract

The cerebellar primordium develops dorsally at an intermediate anteroposterior (AP) level of the neural tube. Its size is modulated by the early anteriorizing and posteriorizing signals, which pattern the neural tube. Two important signaling centers, the midbrain–hindbrain organizer and the roof plate, intersect at the level of the cerebellar anlage and control its positioning, differentiation, growth, survival, and patterning. Neural tube bending in the pontine region induces a widening of the fourth ventricle, which is made possible by choroid plexus differentiation and extension. As a consequence of these morphogenetic changes, the AP axis of the cerebellar primordium is rotated by 90°, and the cerebellar vermis and hemispheres derive from the anterior and posterior parts of the early cerebellar plate, respectively. The cerebellar plate is progressively subdivided along its dorsoventral axis into distinct domains, which generate subsets of cerebellar neurons according to their neurotransmitter phenotype. The roof plate marked by Gdf7 expression is at the origin of choroid plexus cells but does not contribute neurons or glia to the cerebellum. The rhombic lip, marked by Atoh1 expression, produces all the glutamatergic neurons of the cerebellum and a large number of non-cerebellar neurons. Finally, the ventral cerebellar neuroepithelium, marked by Ptf1a expression, generates all the GABAergic neurons and can be further subdivided into two progenitor domains, devoted to the production of Purkinje cells and GABAergic projection neurons of the deep cerebellar nuclei. The so-called cerebellar primordium is not restricted to the production of cerebellar neurons but contributes to a large number of nuclei in the isthmic region.

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References

  • Agoston Z, Schulte D (2009) Meis2 competes with the Groucho co-repressor Tle4 for binding to Otx2 and specifies tectal fate without induction of a secondary midbrain-hindbrain boundary organizer. Development 136:3311–3322

    Article  PubMed  CAS  Google Scholar 

  • Altman J, Bayer SA (1997) Development of the cerebellar system: in relation to its evolution, structure, and functions. CRC Press, Boca Raton, FL

    Google Scholar 

  • Alvarado-Mallart RM, Martinez S, Lance-Jones CC (1990) Pluripotentiality of the 2-day-old avian germinative neuroepithelium. Dev Biol 139:75–88

    Article  PubMed  CAS  Google Scholar 

  • Awatramani R, Soriano P, Rodriguez C et al (2003) Cryptic boundaries in roof plate and choroid plexus identified by intersectional gene activation. Nat Genet 35:70–75

    Article  PubMed  CAS  Google Scholar 

  • Anderson SA, Eisenstat DD, Shi L, Rubenstein JL (1997) Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. Science 278:474–476

    Article  PubMed  CAS  Google Scholar 

  • Basson MA, Echevarria D, Ahn CP et al (2008) Specific regions within the embryonic midbrain and cerebellum require different levels of FGF signaling during development. Development 135:889–898

    Article  PubMed  CAS  Google Scholar 

  • Ben-Arie N, Bellen HJ, Armstrong DL et al (1997) Math1 is essential for genesis of cerebellar granule neurons. Nature 390:169–172

    Article  PubMed  CAS  Google Scholar 

  • Broccoli V, Boncinelli E, Wurst W (1999) The caudal limit of Otx2 expression positions the isthmic organizer. Nature 401:164–168

    Article  PubMed  CAS  Google Scholar 

  • Chizhikov VV, Lindgren AG, Currle DS et al (2006) The roof plate regulates cerebellar cell-type specification and proliferation. Development 133:2793–2804

    Article  PubMed  CAS  Google Scholar 

  • Crossley PH, Martinez S, Martin GR (1996) Midbrain development induced by FGF8 in the chick embryo. Nature 380:66–68

    Article  PubMed  CAS  Google Scholar 

  • Dymecki SM, Kim JC (2007) Molecular neuroanatomy’s “Three Gs”: a primer. Neuron 54:17–34

    Article  PubMed  CAS  Google Scholar 

  • Farago AF, Awatramani RB, Dymecki SM (2006) Assembly of the brainstem cochlear nuclear complex is revealed by intersectional and subtractive genetic fate maps. Neuron 50:205–218

    Article  PubMed  CAS  Google Scholar 

  • Fink AJ, Englund C, Daza RA et al (2006) Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip. J Neurosci 26:3066–3076

    Article  PubMed  CAS  Google Scholar 

  • Gavalas A, Davenne M, Lumsden A et al (1997) Role of Hoxa-2 in axon pathfinding and rostral hindbrain patterning. Development 124:3693–3702

    PubMed  CAS  Google Scholar 

  • 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 108:19–31

    PubMed  CAS  Google Scholar 

  • Hamburger V, Hamilton HL (1951) A series of normal stages in the development of the chick embryo. J Morphol 88:49–92

    Article  Google Scholar 

  • Hoshino H, Nakamura S, Mori K et al (2005) Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron 47:201–213

    Article  PubMed  CAS  Google Scholar 

  • Hoshino M (2006) Molecular machinery governing GABAergic neuron specification in the cerebellum. Cerebellum 5:193–198

    Article  PubMed  CAS  Google Scholar 

  • Irving C, Mason I (2000) Signalling by FGF8 from the isthmus patterns anterior hindbrain and establishes the anterior limit of Hox gene expression. Development 127:177–186

    PubMed  CAS  Google Scholar 

  • Itoh M, Kudoh T, Dedekian M et al (2002) A role for iro1 and iro7 in the establishment of an anteroposterior compartment of the ectoderm adjacent to the midbrain-hindbrain boundary. Development 129:2317–2327

    PubMed  CAS  Google Scholar 

  • Kala K, Jukkola T, Pata I et al (2008) Analysis of the midbrain-hindbrain boundary cell fate using a boundary cell-specific Cre-mouse strain. Genesis 46:29–36

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi D, Kobayashi M, Matsumoto K et al (2002) Early subdivisions in the neural plate define distinct competence for inductive signals. Development 129:83–93

    PubMed  CAS  Google Scholar 

  • Le Douarin N (1982) The neural crest. Cambridge University Press, Cambridge

    Google Scholar 

  • Li JY, Joyner AL (2001) Otx2 and Gbx2 are required for refinement and not induction of mid-hindbrain gene expression. Development 128:4979–4991

    PubMed  CAS  Google Scholar 

  • Liu A, Joyner AL (2001) Early anterior/posterior patterning of the midbrain and cerebellum. Annu Rev Neurosci 24:869–896

    Article  PubMed  CAS  Google Scholar 

  • MacArthur CA, Lawshé A, Xu J et al (1995) FGF-8 isoforms activate receptor splice forms that are expressed in mesenchymal regions of mouse development. Development 121:3603–3613

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Maricich SM, Herrup K (1999) Pax-2 expression defines a subset of GABAergic interneurons and their precursors in the developing murine cerebellum. J Neurobiol 41:281–294

    Article  PubMed  CAS  Google Scholar 

  • Marin F, Puelles L (1995) Morphological fate of rhombomeres in quail/chick chimeras: a segmental analysis of hindbrain nuclei. Eur J Neurosci 7:1714–1738

    Article  PubMed  CAS  Google Scholar 

  • Martinez S, Alvarado-Mallart RM (1989) Rostral cerebellum originates from the caudal portion of the so-called “Mesencephalic” vesicle: a study using chick/quail chimeras. Eur J Neurosci 1:549–560

    Article  PubMed  Google Scholar 

  • Martinez S, Alvarado-Mallart RM (1990) Expression of the homeobox Chick-en gene in chick/quail chimeras with inverted mes-metencephalic grafts. Dev Biol 139:432–436

    Article  PubMed  CAS  Google Scholar 

  • 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 6:971–981

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto K, Nishihara S, Kamimura M et al (2004) The prepattern transcription factor Irx2, a target of the FGF8/MAP kinase cascade, is involved in cerebellum formation. Nat Neurosci 7:605–612

    Article  PubMed  CAS  Google Scholar 

  • McMahon AP, Joyner AL, Bradley A et al (1992) 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

    Article  PubMed  CAS  Google Scholar 

  • Millet S, Bloch-Gallego E, Simeone A et al (1996) The caudal limit of Otx2 gene expression as a marker of the midbrain/hindbrain boundary: a study using in situ hybridisation and chick/quail homotopic grafts. Development 122:3785–3797

    PubMed  CAS  Google Scholar 

  • Millet S, Campbell K, Epstein DJ et al (1999) A role for Gbx2 in repression of Otx2 and positioning the mid/hindbrain organizer. Nature 401:161–164

    Article  PubMed  CAS  Google Scholar 

  • Minaki Y, Nakatani T, Mizuhara E et al (2008) Identification of a novel transcriptional corepressor, Corl2, as a cerebellar Purkinje cell-selective marker. Gene Expr Patterns 8:418–423

    Article  PubMed  CAS  Google Scholar 

  • Mizuhara E, Minaki Y, Nakatani T et al (2010) Purkinje cells originate from cerebellar ventricular zone progenitors positive for Neph3 and E-cadherin. Dev Biol 338:202–214

    Article  PubMed  CAS  Google Scholar 

  • Olsen SK, Li JY, Bromleigh C et al (2006) Structural basis by which alternative splicing modulates the organizer activity of FGF8 in the brain. Genes Dev 20:185–198

    Article  PubMed  CAS  Google Scholar 

  • Pascual M, Abasolo I, Mingorance-Le Meur A et al (2007) Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression. Proc Natl Acad Sci USA 104:5193–5198

    Article  PubMed  CAS  Google Scholar 

  • Raible F, Brand M (2004) Divide et Impera–the midbrain-hindbrain boundary and its organizer. Trends Neurosci 27:727–734

    Article  PubMed  CAS  Google Scholar 

  • Reim G, Brand M (2002) Spiel-ohne-grenzen/pou2 mediates regional competence to respond to Fgf8 during zebrafish early neural development. Development 129:917–933

    PubMed  CAS  Google Scholar 

  • Rodriguez CI, Dymecki SM (2000) Origin of the precerebellar system. Neuron 27:475–486

    Article  PubMed  CAS  Google Scholar 

  • Sato T, Araki I, Nakamura H (2001) Inductive signal and tissue responsiveness defining the tectum and the cerebellum. Development 128:2461–2469

    PubMed  CAS  Google Scholar 

  • Sato T, Joyner AL (2009) The duration of Fgf8 isthmic organizer expression is key to patterning different tectal-isthmo-cerebellum structures. Development 136:3617–3626

    Article  PubMed  CAS  Google Scholar 

  • Sgaier SK, Millet S, Villanueva MP et al (2005) Morphogenetic and cellular movements that shape the mouse cerebellum; insights from genetic fate mapping. Neuron 45:27–40

    PubMed  CAS  Google Scholar 

  • Simeone A (2000) Positioning the isthmic organizer where Otx2 and Gbx2meet. Trends Genet 16:237–240

    Article  PubMed  CAS  Google Scholar 

  • Urbánek P, Fetka I, Meisler MH et al (1997) Cooperation of Pax2 and Pax5 in midbrain and cerebellum development. Proc Natl Acad Sci USA 94:5703–5708

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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  PubMed  CAS  Google Scholar 

  • Wassarman KM, Lewandoski M, Campbell K et al (1997) Specification of the anterior hindbrain and establishment of a normal mid/hindbrain organizer is dependent on Gbx2 gene function. Development 124:2923–2934

    PubMed  CAS  Google Scholar 

  • Wonders CP, Anderson SA (2006) The origin and specification of cortical interneurons. Nat Rev Neurosci 7:687–696

    Article  PubMed  CAS  Google Scholar 

  • Wurst W, Auerbach AB, Joyner AL (1994) Multiple developmental defects in Engrailed-1 mutant mice: an early mid-hindbrain deletion and patterning defects in forelimbs and sternum. Development 120:2065–2075

    PubMed  CAS  Google Scholar 

  • Wurst W, Bally-Cuif L (2001) Neural plate patterning: upstream and downstream of the isthmic organizer. Nat Rev Neurosci 2:99–108

    Article  PubMed  CAS  Google Scholar 

  • Ye W, Bouchard M, Stone D et al (2001) Distinct regulators control the expression of the mid-hindbrain organizer signal FGF8. Nat Neurosci 4:1175–1181

    Article  PubMed  CAS  Google Scholar 

  • Yu T, Yaguchi Y, Echevarria D et al (2011) Sprouty genes prevent excessive FGF signaling in multiple cell types throughout development of the cerebellum. Development 138:2957–2968

    Article  PubMed  CAS  Google Scholar 

  • Zervas M, Blaess S, Joyner AL (2005) Classical embryological studies and modern genetic analysis of midbrain and cerebellum development. Curr Top Dev Biol 69:101–138

    Article  PubMed  CAS  Google Scholar 

  • Zinyk DL, Mercer EH, Harris E et al (1998) Fate mapping of the mouse midbrain-hindbrain constriction using a site-specific recombination system. Curr Biol 8:665–668

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Marion Wassef .

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Wassef, M. (2013). Specification of the Cerebellar Territory. In: Manto, M., Schmahmann, J.D., Rossi, F., Gruol, D.L., Koibuchi, N. (eds) Handbook of the Cerebellum and Cerebellar Disorders. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-1333-8_1

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