Our long-term goals are to establish molecular links between the functional organization of the visual system and the developmental mechanisms through which it is formed. We have identified a candidate for such a link in the vitamin A pathway. Retinoids are known to serve two roles in vertebrates: 11-cis retinaldehyde forms the chromophore of visual pigments, and retinoic acid (RA) regulates gene transcription throughout the body. We find that these two roles are connected in the eye. In previous and preliminary observations, we discovered highly intricate expression patterns of different RA-generating aldehyde dehydrogenases in the developing and mature eye, and in the functioning eye we found that light causes an increase in RA. We propose to test the hypothesis that RA, generated by the aldehyde dehydrogenases, is involved in several aspects of the development and diseases of the eye. Our goals are (1) to test the hypothesis that the dorso-ventral axis of the retina is set up by dynamic expression patterns of retinoid metabolizing enzymes in the eye anlage; (2) to perturb normal RA levels in the eye anlage of the mouse embryo; (3) to analyze the function of aldehyde dehydrogenases; and (4) to screen for novel aldehyde dehydrogenases both in the embryonic mouse and in human eyes. These projects are relevant to understanding the mechanisms of some inborn and postnatal eye diseases in humans. Many severe idiopathic eye malformations originate from the ventral eye or the optic fissure, similar to the ventral eye defects in vitamin A deficiency. In the postnatal human retina, different forms of sectoral retinitis pigmentosa show photoreceptor degenerations in patterns that resemble the distribution of the aldehyde dehydrogenases in the mouse. Thus, we seek to confirm that similar patterns exist in humans. We hypothesize that the very high expression of aldehyde dehydrogenases in the eye reflects their ancient function as detoxifying enzymes necessary to protect the eye from light damage; and that RA, formed from retinaldehyde as a minor by-product of the visual cycle, then gained transcriptional control over multiple ocular processes. An origin of the transcriptional role of RA from vision may explain the known vulnerability of the developing and mature eye to vitamin A disturbances.
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