RESUMEN
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.
Asunto(s)
Encéfalo/embriología , Organizadores Embrionarios/fisiología , Proteínas Supresoras de Tumor/metabolismo , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Animales , Tipificación del Cuerpo/fisiología , Encéfalo/anomalías , Encéfalo/metabolismo , Embrión no Mamífero/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Mesencéfalo/anomalías , Mesencéfalo/embriología , Mesencéfalo/metabolismo , Mutación , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Wnt/fisiología , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
The tumor suppressor Apc1 is an intracellular antagonist of the Wnt/beta-catenin pathway. We examined the effects of an Apc1 loss-of-function mutation on retino-tectal axon pathfinding in zebrafish. In apc mutants, the retina is disorganized and optic nerves portray pathfinding defects at the optic chiasm and do not project properly to the tectum. Wild-type cells, transplanted into mutant retinae, acquire retinal ganglion cell fate and project axons that cross at the mispositioned optic chiasm and extend to the contralateral tectum, suggesting a function of apc1 in axon pathfinding. These defects are caused mainly by stabilization of beta-catenin. These data demonstrate that Apc1 function is required for correct patterning of the retina and proper retinal ganglion axon projections.