New Mouse Models of Microphthamia

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DESCRIPTION (provided by applicant): Congenital eye defects are relatively common and oftentimes impair vision or cause blindness. Microphthalmia is a severe congenital eye defect in which the eye fails to grow to its normal size, among other problems. Because the onset of microphthalmia occurs early in fetal development, very little is known about its primary causes or the changes that occur in human eye development. In the past few years, several genes have been conclusively linked to microphthalmia in humans. One of them, Chx10, causes non-syndromic, bilateral microphthalmia and children with this condition are born blind. Three missense mutations have been identified, but the progression of ocular development in humans with these mutations is not known. The primary goal of these studies is to characterize the developmental phenotypes caused by the mutations in Chx10 that are founding humans. Our approach is to produce two of the three human mutations in the mouse using transgenic knock-in technology and characterize the resulting phenotypes. Phenotypes will be determined in embryos, neonates, and adult mice by histological methods including in situ hybridization and immunohistochemistry. Completion of these studies could provide significant insight into the developmental changes associated with microphthalmia in humans and further resolve the role of Chx10 in eye formation, and in particular, retinal development. Congenital eye anomalies are relatively common birth defects that cause visual impairments or blindness. Microphthalmia, or small eye, is a severe anomaly for which there is no available corrective treatment. Three mutations in the Chx10 gene cause micropthalmia in humans. We have generated mouse models that carry two of the human mutations and an important goal of this grant is to characterize the defects that occur during eye development in order to better understand the etiology of human microphthalmia.