Retinoic acid (RA) is a metabolic derivative of vitamin A (retinol) that functions as a signaling molecule. RA is essential for eye development, but its action is poorly understood. RA signaling occurs when retinol is metabolized to RA which serves as a ligand for nuclear RA receptors that regulate gene expression. The enzymes controlling synthesis of RA during embryogenesis are now under investigation and such studies are providing new information on the mechanism of RA action during eye development. Studies on mouse embryos have demonstrated the existence of three retinaldehyde dehydrogenases differentially expressed in the eye that synthesize RA, i.e. RALDH1, RALDH2, and RALDH3. Investigations of Raldh1, Raldh2, and Raldh3 null mutant mice have uncovered eye defects, and further studies of these mice are beginning to reveal the mechanism of RA action. As the three Raldh genes are conserved in mice and humans, the null mutants we have developed are excellent mouse models for understanding the mechanism of RA action during human eye development. Evidence exists suggesting that RA deficiency caused by dietary vitamin A deficiency may be linked to the human eye defect known as ocular coloboma. The genetic studies proposed will provide information relevant to treatment of human eye diseases whose etiology involves genetic deficiency in RA synthesis and/or dietary vitamin A deficiency: We have found that the location of RA synthesis undergoes dynamic spatiotemporal changes during eye development, and that the location of RA action changes in synchrony. Raldh2/Raldh3 double mutant mouse embryos develop an optic vesicle, but this structure lacks RA synthesis and fails to invaginate ventrally to form the optic cup. Raldh3 null mutant embryos develop an optic cup but they display defects in closure of the optic fissure (coloboma). Raldhl null mutant embryos lack RA synthesis in the dorsal retina, but eye defects are not observed. However, Raldh1/Raldh3 double mutants display excessive invasion of perioptic mesenchyme anterior to the retina, thus revealing a function for Raldhl that is normally compensated by Raldh3 (and vice-versa). These findings have led to the hypothesis that RA controls eye morphogenetic movements rather than dorsoventral patterning of the retina as previously thought. The overall goal of this project is to determine the mechanism of RA signaling during eye development, particularly the gene networks regulated by RA in the eye. We will test the hypothesis that RA regulates eye morphogenetic movements of both the retina and the surrounding perioptic mesenchyme. These studies will be performed genetically using Raldh compound null mutant mice that are unrescued or rescued by various genetic or pharmacological methods. Specific investigations will focus upon: (1) RA control of cell shape and cell adhesion during optic cup formation;(2) RA-FGF antagonism during optic cup formation;(3) RA control of perioptic mesenchyme invasion following optic cup formation.
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