A zebrafish genetic model to search for novel genes involved in the aetiology of ocular malformations (360G-Wellcome-213928_Z_18_Z)

Anophthalmia, microphthalmia and coloboma arise from defects in eye morphogenesis and are amongst the most severe defects associated with blindness. Some of the genes affected in these conditions have been identified, but in most cases the causes underlying these congenital malformations are unknown. Often mutations in genes relevant for eye formation may not display defective phenotypes by themselves and their potential relevance to understand eye malformations in humans is overlooked. A strategy to identify those genes is to perform searches in a genetic background sensitised to eye malformations. This project aims at validating a genetic model that will be used for such purpose. Frizzled5 is a Wnt receptor expressed at several stages during eye morphogenesis. A mutation in fzd5 that interferes in a dominant-negative way with Wnt signalling has been described in families with microphthalmia/coloboma. However, fzd5 loss of function in animal models is phenotypically normal, probably due to functional compensation by other receptors. Our preliminary analysis indicates that despite their lack of eye defects, fzd5 zebrafish mutants show compromised Wnt activity. Here we will extend this analysis and will provide the basis to establish fzd5 mutants as a sensitised condition to identify novel genes involved in eye malformations.