RAR-BETA ISOFORMS - DISTINCT TRANSCRIPTIONAL CONTROL BY RETINOIC ACID AND SPECIFIC SPATIAL PATTERNS OF PROMOTER ACTIVITY DURING MOUSE EMBRYONIC-DEVELOPMENT

That both deficiency and excess of vitamin A lead to a wide spectrum of congenital abnormalities has strongly implicated the active metabolite, retinoic acid (RA), in normal embryonic development. There are 3 families of RA receptors (RARs), RARalpha, RARbeta and RARgamma, each having at least two isoforms derived from primary transcripts initiated at two promoters Pl and P2 (reviewed in Leid et al., 1992) Transcripts encoding all 4 isoforms of RARbeta (RARbeta1 to RARbeta4) accumulate in embryonal carcinoma (EC) cells in the presence of RA. It has been previously shown that the RA modulation of RARbeta2/beta4 transcripts is achieved at the level of transcriptional initiation via a RA response element (RARE) present in the P2 RARbeta2/beta4 promoter. In contrast, the mechanism by which RA up-regulates RARbeta1/beta3 transcripts has not yet been elucidated. We describe here the isolation of the PI RARbeta1/beta3 promoter and characterization of its activity in transgenic animals. We find that RARbeta1/beta3 promoter activity, which is apparently confined to the embryonic CNS, is not modified by RA treatment, unlike that of the RARbeta2/beta4 promoter (Mendelsohn et al., 1991). Nuclear run-on transcription analysis in EC cells supports the conclusion that RARbeta1/beta3 transcript initiation is not modulated by RA, and that the RA-induced accumulation of RARbeta1/beta3 transcripts occur via a RA-dependent release of a block in RNA chain elongation.