TRANSGENIC MODELS OF RETINOID TOXICOLOGY & TERATOGENESIS

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DESCRIPTION: Retinoic acid (RA) is the biologically active derivative of vitamin A and deficiencies of vitamin A lead to pathologies involving tissue degeneration. RA treatment reverses many of the pathological processes. Embryonic exposure to high levels of RA at gastrulation is teratogenic. Furthermore, a number of gene families are activated by RA, including the Hox gene family. This project endeavors to further characterize the molecular biology of retinoid- and RA-induced toxicology and teratogenesis, using transgenic mouse models. This proposal involves using various transgenic mouse models to examine the effects of toxic doses of RA on the regulation of Hoxa-1 and Hoxa-2 gene expression during critical stages of fetal development. The correct spatiotemporal patterns of expression of these homeobox-containing genes are critical for the normal development of the craniofacial and other head regions. Since the same regions are affected by teratogenic doses of retinoic acid, and since a newly discovered retinoic acid response element (RARE) has been found at the 3' end of the Hox gene group, there is a strong possibility that retinoic acid exerts its toxic effects through directing the ectopic expression of these genes. The principal investigator intends to first identify putative regulatory regions of these genes and then, by site directed mutagenesis, to test the functions of binding sites of regulatory factors in transgenic mice. The next phase involves the role of the RARE in Hoxa-1 and Hoxa-2 expression in development using a knockout model. Lastly, they intend to examine Hoxa-1 contribution to the phenotype seen in retinoid toxicity by giving Hoxa-1 knockout mice toxic doses of RA. As part of this last goal, they also want to look at changes in Hox expression in retinoic acid receptor (RAR) knockout mice.