Growing evidence indicates that retinoic acid, an oxidized derivative of vitamin A, is required for cells to commit to a neuronal phenotype. Nuclear retinoic acid receptors (RARs) and enzymes with the capacity to synthesize a retinoic acid persist in terminally-differentiated neural tissues such as adult eye and brain, and relatively high levels of retinoic acid have been measured in adult neural retina. Thus, it is likely that retinoic acid is functional in mature neuronal cells, perhaps influencing them to maintain their terminally-differentiated state. Recent results obtained from studies of double null mutant mice lacking RAP- beta2/RAR-gamma2 indicate a lack of photoreceptor differentiation, histologic defects in the retinal pigment epithelium, retinal dysplasia, and degeneration of the adult neural retina (Grondona et el. 1996). These results support the idea that RARs, presumably via interactions with vitamin A derivatives such as retinoic acid, stimulate neurogenesis and are involved in maintaining the integrity and function of adult retinal cells. It is of scientific and clinical interest to characterize the molecular basis for the involvement of vitamin V derivatives in processes affecting the maturation and maintenance of sensory neurons. The principal investigator proposes to investigate the nature of this involvement by (1) using an immunohistochemical approach to determine whether vitamin A status influence the differentiation and/or maturation of olfactory neurons (adult olfactory epithelium retains the ability to generate neurons throughout adult life), and (2) using a subtractive hybridization approach, to characterize the types and identities of genes that are regulated by vitamin A status in a continuously-differentiating (olfactory epithelium) and two terminally-differentiated (eye and brain) adult, neural tissues. Comparison of affected genes in eye, brain, and olfactory tissue will indicate whether vitamin A status regulates specific types of genes in regenerative and on-regenerative neural tissues. The results of the proposed studies will contribute to our fundamental understanding of processes that control normal neural development and function and will provided a basis for determining the mechanisms that underlie pathologies associated with neurodegenerative disease.
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