Retinoic acid regulation of Cdx1: an indirect mechanism for retinoids and vertebral specification

Retinoic acid (RA) is required for diverse developmental programs, includin g vertebral specification. Both RA receptor disruption and excess RA result in homeotic transformations of the axial skeleton. These effects are belie ved to occur through altered expression of Hox genes, several of which have been demonstrated to be direct RA targets. Members of the cdx (caudal) hom eobox gene family are also implicated in regulating Hox expression. Disrupt ion of cdx1 results in vertebral homeotic transformations and alteration of Hox expression boundaries; similar homeosis is also observed in cdx2 heter ozygotes, In Xenopus, gain or loss of Cdx function affects vertebral morpho genesis through a mechanism that also correlates with altered Hox expressio n. Taken together with the finding of putative Cdx binding motifs in severa l Hox promoters, these data strongly support a role for Cdx members in dire ct regulation of expression of at least some Hox genes. Most retinoid-respo nsive Hox genes have not been demonstrated to be direct RA targets, suggest ing that intermediaries are involved. Based on these findings, we hypothesi zed that one or more cdx members may transduce the effects of RA on Hox tra nscription. Consistent,vith this, we present evidence that cdx1 is a direct RA target gene, suggesting an additional pathway for retinoid-dependent ve rtebral specification.