Microphthalmia and Disrupted Retinal Development Due to a Knock-in/knock-out Allele at the Locus

Visual System Homeobox 2 () is a transcription factor expressed in the developing retina that regulates tissue identity, growth, and fate determination. Several mutations in the gene exist in mice, including a spontaneous nonsense mutation and two targeted missense mutations originally identified in humans. Here, we expand the genetic repertoire to include a reporter allele ( ) designed to express beta-Galactosidase (b-GAL) and simultaneously disrupt function (knock-in/knock-out). The retinal expression pattern of b-GAL is concordant with VSX2, and the mutant allele is recessive. homozygous mice have congenital bilateral microphthalmia accompanied by defects in retinal development including ectopic expression of non-retinal genes, reduced proliferation, delayed neurogenesis, aberrant tissue morphology, and an absence of bipolar interneurons - all hallmarks of loss-of-function. Unexpectedly, the mutant VSX2 protein is stably expressed, and there are subtle differences in eye size and early retinal neurogenesis when compared to the null mutant, . The perdurance of the mutant VSX2 protein combined with subtle deviations from the null phenotype leaves open the possibility that allele is not a complete knock-out. The allele exhibits loss-of-function characteristics and adds to the genetic toolkit for understanding function.