The direct context of a hox retinoic acid response element is crucial for its activity.
During embryogenesis, target genes of retinoid signaling are able to respond differently to identical concentrations of retinoids. Small differences in the retinoic acid response elements (RARE) may be essential for these distinct responses. Recently, we identified a RARE in a Hox enhancer (dubbed distal element) that is active relatively late during mouse development. We now show that the RARE motif in the distal element is necessary and sufficient for the induction of gene expression by retinoic acid (RA) in P19 embryonic carcinoma cells. Furthermore, the significance of these results was established by RA treatment of transgenic mouse lines carrying the distal element containing the wild-type or a mutated RARE. We compared the in vitro activity of the distal element-RARE with that of the direct repeat with 5-bp spacer RARE of the RARbeta2 gene, which is active during early during mouse development. We found that these RAREs, despite their similarity, responded differently to RA. By making single point mutations we show that the specificity resides in their retinoid X receptor-binding sites and is determined by base pairs located just outside the RARE consensus sequence. We suggest that the context of RARE motifs is important for the distinct transcriptional activities of genes under control of retinoid signaling.
Oosterveen
Tony
T
Hubrecht Laboratory, The Netherlands Institute of Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
van Vliet
Patrick
P
Deschamps
Jacqueline
J
Meijlink
Frits
F
D000818:Animals; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000235:genetics*; D005801:Genes, Homeobox; D017930:Genes, Reporter; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology; D020218:Response Elements / Q000235:genetics / Q000502:physiology*; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin / Q000502:physiology*
D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; C082925:retinoic acid receptor beta; D014212:Tretinoin