title: Apc1 is required for maintenance of local brain organizers and dorsal midbrain survival.
abstract: The tumor suppressor Apc1 is an intracellular antagonist of the Wnt/beta-catenin pathway, which is vital for induction and patterning of the early vertebrate brain. However, its role in later brain development is less clear. Here, we examined the mechanisms underlying effects of an Apc1 zygotic-effect mutation on late brain development in zebrafish. Apc1 is required for maintenance of established brain subdivisions and control of local organizers such as the isthmic organizer (IsO). Caudal expansion of Fgf8 from IsO into the cerebellum is accompanied by hyperproliferation and abnormal cerebellar morphogenesis. Loss of apc1 results in reduced proliferation and apoptosis in the dorsal midbrain. Mosaic analysis shows that Apc is required cell-autonomously for maintenance of dorsal midbrain cell fate. The tectal phenotype occurs independently of Fgf8-mediated IsO function and is predominantly caused by stabilization of beta-catenin and subsequent hyperactivation of Wnt/beta-catenin signalling, which is mainly mediated through LEF1 activity. Chemical activation of the Wnt/beta-catenin in wild-type embryos during late brain maintenance stages phenocopies the IsO and tectal phenotypes of the apc mutants. These data demonstrate that Apc1-mediated restriction of Wnt/beta-catenin signalling is required for maintenance of local organizers and tectal integrity.
authors.affiliation: Hubrecht Institute, University Medical Center Utrecht, The Netherlands.
authors.forename: Judith T M L
authors.initials: JT
authors.lastname: Paridaen
authors.forename: Catherine
authors.initials: C
authors.lastname: Danesin
authors.forename: Abu Tufayal
authors.initials: AT
authors.lastname: Elas
authors.forename: Sandra
authors.initials: S
authors.lastname: van de Water
authors.forename: Corinne
authors.initials: C
authors.lastname: Houart
authors.forename: Danica
authors.initials: D
authors.lastname: Zivkovic
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000502:physiology; D001921:Brain / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D008636:Mesencephalon / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D009154:Mutation; D020897:Organizers, Embryonic / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000502:physiology; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C507321:LEF1 protein, zebrafish; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C541913:apc protein, zebrafish; D051176:beta Catenin; C517774:fgf8a protein, zebrafish; D005346:Fibroblast Growth Factors