TARGETED DISRUPTION OF RETINOIC ACID RECEPTOR-ALPHA (RAR-ALPHA) AND RAR-GAMMA RESULTS IN RECEPTOR-SPECIFIC ALTERATIONS IN RETINOIC ACID-MEDIATED DIFFERENTIATION AND RETINOIC ACID METABOLISM

F9 embryonic teratocarcinoma stem cells differentiate into an epitheli al cell type called extraembryonic endoderm when treated with retinoic acid (RA), a derivative of retinol (vitamin A),This differentiation i s presumably mediated through the actions of retinoid receptors, the R ARs and RXRs, To delineate the functions of each of the different reti noid receptors in this model system, we have generated F9 cell lines i n which both copies of either the RAR alpha gene or the RAR gamma gene are disrupted by homologous recombination, The absence of RAR alpha i s associated with a reduction in the RA-induced expression of both the CRABP-II and Hoxb-1 (formerly 2.9) genes. The absence of RAR gamma is associated with a loss of the RA-inducible expression of the Hoxa-1 ( formerly Hox-1,6), Hoxa-3 (formerly Hox-1.5), laminin B1, collagen IV( alpha 1), GATA-4, and BMP-2 genes, Furthermore, the loss of RAR gamma is associated with a reduction in the metabolism of all-trans-RA to mo re polar derivatives, while the loss of RAR alpha is associated with a n increase in metabolism of RA relative to wild-type F9 cells, Thus, e ach of these RARs exhibits some specificity with respect to the regula tion of differentiation-specific gene expression. These results provid e an explanation for the expression of multiple RAR types within one c ell type and suggest that each RAR has specific functions.