Genetic defects of vision are a common cause of blindness in children. Such defects include gross developmental anomalies such as anophthalmia and microphthalmia, optic nerve hypoplasia, coloboma, and inherited retinal degenerations. Microphthalmia and associated birth defects accounts for 1 to 1.9 per 10,000 live births worldwide. The socio-economic consequences and healthcare impact are obvious. Up to 80% of microphthalmic cases occur as part of over 100 genetic syndromes. These anomalies that are frequently associated with microphthalmia include coloboma, craniofacial, skeletal, renal, and cardiac defects. Nevertheless, molecular mechanisms that lead to these dire conditions are largely unknown. Recent studies in both avian and murine systems have shown that diffusible factors such as Bone morphogenetic proteins (BMPs) signal transduction pathway may be important regulatory components that regulate not only the size but also the polarity of the vertebrate eye. There are also compelling evidence showing that these signaling pathways are important in regulating the differentiation processes of retinal ganglion cells (RGCs) in the neuroretina and in maintaining the laminar structure of postnatal retinas. However, how these signaling molecules influence transcriptional events in the cell nucleus are largely unexplored. The current proposal is to establish the Msx2 gene as a key component of BMP signaling in controlling optic cup formation. The long-term goal of this project is to elucidate the molecular mechanisms underlying some pediatric ocular anomalies, such as microphthalmia, coloboma and associated ocular malformations. Developmental paradigms have always guided our quest for the understanding of disease processes. Integration of various signaling mechanisms will significantly advance our understanding of genetic control mechanisms that govern normal eye development and pathogenesis. This insight is essential for the development of new approaches to disease management and rational therapies. We believe that the analysis of the ocular malformation in the Msx2 transgenic animals will provide a plausible molecular explanation on how pediatric anomalies including microphthalmia and coloboma may arise. By targeting BMP signaling and its upstream and downstream mediators, one may find a fertile ground for detecting mutations that cause syndromic microphthalmia. ? ? ?
