title: Independently specified Atoh1 domains define novel developmental compartments in rhombomere 1.
abstract: The rhombic lip gives rise to neuronal populations that contribute to cerebellar, proprioceptive and interoceptive networks. Cell production depends on the expression of the basic helix-loop-helix (bHLH) transcription factor Atoh1. In rhombomere 1, Atoh1-positive cells give rise to both cerebellar neurons and extra-cerebellar nuclei in ventral hindbrain. The origin of this cellular diversity has previously been attributed to temporal signals rather than spatial patterning. Here, we show that in both chick and mouse the cerebellar Atoh1 precursor pool is partitioned into initially cryptic spatial domains that reflect the activity of two different organisers: an isthmic Atoh1 domain, which gives rise to isthmic nuclei, and the rhombic lip, which generates deep cerebellar nuclei and granule cells. We use a combination of in vitro explant culture, genetic fate mapping and gene overexpression and knockdown to explore the role of isthmic signalling in patterning these domains. We show that an FGF-dependent isthmic Atoh1 domain is the origin of distinct populations of Lhx9-positive neurons in the extra-cerebellar isthmic nuclei. In the cerebellum, ectopic FGF induces proliferation while blockade reduces the length of the cerebellar rhombic lip. FGF signalling is not required for the specification of cerebellar cell types from the rhombic lip and its upregulation inhibits their production. This suggests that although the isthmus regulates the size of the cerebellar anlage, the downregulation of isthmic FGF signals is required for induction of rhombic lip-derived cerebellar neurons.
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, 4th floor New Hunt's House, London SE1 1UL, UK.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Green
authors.forename: Anna M
authors.initials: AM
authors.lastname: Myat
authors.forename: Brian A
authors.initials: BA
authors.lastname: Emmenegger
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
authors.forename: Leigh J
authors.initials: LJ
authors.lastname: Wilson
authors.forename: Richard J T
authors.initials: RJ
authors.lastname: Wingate
mesh_terms: D000818:Animals; D030161:Avian Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002531:Cerebellum / Q000196:embryology* / Q000378:metabolism*; D002642:Chick Embryo; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008636:Mesencephalon / Q000196:embryology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D051857:Otx Transcription Factors / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D012249:Rhombencephalon / Q000196:embryology / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D030161:Avian Proteins; D051792:Basic Helix-Loop-Helix Proteins; D051524:Fibroblast Growth Factor 8; D060850:LIM-Homeodomain Proteins; D051857:Otx Transcription Factors; D014157:Transcription Factors; C500943:Atoh1 protein, mouse; C496457:Fgf8 protein, mouse; C117058:Lhx9 protein, mouse; C497660:Otx2 protein, mouse
keywords: Cerebellum; Chick; Deep cerebellar nuclei; FGF receptor knockout; Gbx2; Isthmo-optic nucleus; Lhx9; Mouse; Otx2