frizzled5 mutant zebrafish are genetically sensitised to developing microphthalmia and coloboma.

Abstract

Microphthalmia and coloboma are structural malformations of the eyes that arise from defective morphogenesis and are amongst the most severe defects associated with paediatric blindness. FZD5 is a Wnt receptor expressed in the developing eye and individuals with mutations in FZD5 exhibit microphthalmia/coloboma supporting a role for this receptor in human eye formation. Here we show that zebrafish fzd5 mutants homozygous for complete loss-of-function or predicted dominant-negative alleles, display no obvious eye defects during embryogenesis. Rather, they develop eye defects comparable to those described in humans only upon simultaneous abrogation of additional genes associated with ocular malformations. Thus, eye development can occur normally in the absence of Fzd5 in zebrafish but mutants are sensitised to developing eye malformations. By exploiting the sensitised nature of the fzd5 mutants we further identified aamp as a novel gene involved in eye morphogenesis. Overall, our study confirms the importance of considering multiple genetic contributions when searching for the molecular aetiology of ocular malformations in humans.