Description) The transcriptional activator retinoic acid (RA) is essential for the normal development of the central nervous system. Defects in either the RA receptors or the enzymes that produce RA result in severe developmental abnormalities. The normal requirement for RA in development explain its teratogenicity and the use of RA for the treatment of acne, psoriasis, and leukemia renders this the most teratogenic compound in use. Disruptions in RA signaling have been suggested to be the basis of several congenital and toxin induced diseases, including Dandy-Walker and Arnold-Chiari malformations, as well as alcohol, dioxin, and PCB teratogenicity. Cerebellar malformations occur in all of these diseases and the investigators propose to study the cerebellar abnormalities in the mouse which result from the application of either an excess or insuffiency of RA. These conditions will be achieved by the use of RA receptor agonists and antagonists, chemical inhibitors of RA synthesis, and the use of viral vectors to misexpress RA synthesizing and catabolic enzymes. The investigators' preliminary data in migration as events that normally require RA. They plan to investigate the distribution of a transgenic reporter gene for RA signaling in the cerebellum; the influence of excess recep6tor ligand on cerebellar ligand on cerebellar development; and the influence of RA signal inhibition of cerebellar development. These results will assist in the identification of cerebellar events normally regulated by RA, as well as provide insights into the etiology of diseases that result from disruption of RA signaling.
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