IN-VIVO FUNCTIONAL-ANALYSIS OF THE HOXA-1 3'-RETINOIC ACID RESPONSE ELEMENT (3'RARE)

Retinoids are essential for normal development and both deficiency and excess of retinoic acid (RA) are teratogenic. Retinoic acid response elements (RAREs) have been identified in Hox gene promoters suggesting that endogenous retinoids may be involved in the direct control of Ho x gene patterning functions, In order to test this hypothesis, we have mutated the Hoxa-1 3'RARE using the Cre-loxP targeting strategy, and studied its functional role during mouse development, We find that thi s enhancer plays an important role in the early establishment of the H oxa-1 anterior expression boundary in the neural plate. This early dis turbance in Hoxa-1 activation results in rhombomere and cranial nerve abnormalities reminiscent of those obtained in the Hoxa-1 total knocko ut, although their severity and penetrance are lower, thus providing s trong evidence for direct control of Hox gene function by retinoids du ring normal development, Interestingly, we also find that the Hoxa-1 e xpression response to RA treatment is not entirely controlled by the R ARE, suggesting the existence of other retinoid-induced factors mediat ing the Hoxa-1 response to RA and/or the presence of additional RAREs, Interestingly, although the RARE is not required for the spatiotempor al control of colinear expression of the Hoxa genes, it is absolutely required for correct Hoxa-2 expression in rhombomere 5.