title: Cerebellar development in the absence of Gbx function in zebrafish.
abstract: The midbrain-hindbrain boundary (MHB) is a well-known organizing center during vertebrate brain development. The MHB forms at the expression boundary of Otx2 and Gbx2, mutually repressive homeodomain transcription factors expressed in the midbrain/forebrain and anterior hindbrain, respectively. The genetic hierarchy of gene expression at the MHB is complex, involving multiple positive and negative feedback loops that result in the establishment of non-overlapping domains of Wnt1 and Fgf8 on either side of the boundary and the consequent specification of the cerebellum. The cerebellum derives from the dorsal part of the anterior-most hindbrain segment, rhombomere 1 (r1), which undergoes a distinctive morphogenesis to give rise to the cerebellar primordium within which the various cerebellar neuron types are specified. Previous studies in the mouse have shown that Gbx2 is essential for cerebellar development. Using zebrafish mutants we show here that in the zebrafish gbx1 and gbx2 are required redundantly for morphogenesis of the cerebellar primordium and subsequent cerebellar differentiation, but that this requirement is alleviated by knocking down Otx. Expression of fgf8, wnt1 and the entire MHB genetic program is progressively lost in gbx1-;gbx2- double mutants but is rescued by Otx knock-down. This rescue of the MHB genetic program depends on rescued Fgf signaling, however the rescue of cerebellar primordium morphogenesis is independent of both Gbx and Fgf. Based on our findings we propose a revised model for the role of Gbx in cerebellar development.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Chen-Ying
authors.initials: CY
authors.lastname: Su
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Kemp
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: cmoens@fhcrc.org.
authors.forename: Cecilia B
authors.initials: CB
authors.lastname: Moens
mesh_terms: D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning; D002454:Cell Differentiation; D002531:Cerebellum / Q000196:embryology* / Q000378:metabolism; D004843:Epistasis, Genetic; D005346:Fibroblast Growth Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009024:Morphogenesis; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D051857:Otx Transcription Factors / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; D051857:Otx Transcription Factors; D029961:Zebrafish Proteins; C517774:fgf8a protein, zebrafish; C486024:gbx1 protein, zebrafish; C513181:gbx2 protein, zebrafish; D005346:Fibroblast Growth Factors
keywords: Cerebellum; Gbx; Zebrafish