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), RAR alpha, RAR beta and RAR gamma, each having at least two isoforms derived from primary transcripts initiated at two promoters P1 and P2 (reviewed in Leid et al., 1992) Transcripts encoding all 4 isoforms of RAR beta (RAR beta 1 to RAR beta 4) accumulate in embryonal carcinoma (EC) cells in the presence of RA. It has been previously shown that the RA modulation of RAR beta 2/beta 4 transcripts is achieved at the level of transcriptional initiation via a RA response element (RARE) present in the P2 RAR beta 2/beta 4 promoter. In contrast, the mechanism by which RA up-regulates RAR beta 1/beta 3 transcripts has not yet been elucidated. We describe here the isolation of the P1 RAR beta 1/beta 3 promoter and characterization of its activity in transgenic animals. We find that RAR beta 1/beta 3 promoter activity, which is apparently confined to the embryonic CNS, is not modified by RA treatment, unlike that of the RAR beta 2/beta 4 promoter (Mendelsohn et al., 1991). Nuclear run-on transcription analysis in EC cells supports the conclusion that RAR beta 1/beta 3 transcript initiation is not modulated by RA, and that the RA-induced accumulation of RAR beta 1/beta 3 transcripts occur via a RA-dependent release of a block in RNA chain elongation.
Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Faculté de Médecine, Strasbourg, France.
C
C
Mendelsohn
S
S
Larkin
M
M
Mark
M
M
LeMeur
J
J
Clifford
A
A
Zelent
P
P
Chambon
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004247:DNA; D005314:Embryonic and Fetal Development / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D015183:Restriction Mapping; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism*; D015854:Up-Regulation
D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D014212:Tretinoin; D004247:DNA