Chicken Ovalbumin Upstream Promoter-Transcription Factor Members Repress Retinoic Acid-induced Cdx1 Expression

Abstract

It is well established that Hox genes are key players in specifying positional identity along the anterior-posterior axis and are targets of diverse transcription factors implicated in axial patterning. Members of the CDX family (CDX1, -2, and -4) are among such effectors of Hox expression as pertains to vertebral patterning in the mouse. Cdx members are themselves targets of signaling molecules that are also implicated in axial patterning, including retinoic acid (RA) and certain members of Wnt and fibroblast growth factor families. In this regard, we have previously shown that, in the mouse, Cdx1 is directly regulated by RA at the late primitive streak stage (embryonic day (E) 7.5) through a RA response element in the proximal Cdx1 promoter. At E8.5, Cdx1 expression remains essentially limited to the posterior embryo. RA, however, is excluded from the caudal embryo at this later stage, but is found in a more anterior domain encompassing the prospective trunk region. These observations suggest the existence of a repressor mechanism that prevents expression of Cdx1 in these anterior domains of retinoid signaling at E8.5. In the present study, we present evidence suggesting that chicken ovalbumin upstream promoter-transcription factor (COUP-TF) members antagonize RA-induced Cdx1 expression by competing with retinoid X receptor-retinoic acid receptor heterodimers for binding to the Cdx1 RA response element. Consistent with this, in situ hybridization analysis revealed that COUP-TFs are highly expressed in the anterior embryo in domains where Cdx1 transcripts are excluded. Together with other data, these findings suggest a model by which COUP-TF expression is induced by RA in the trunk region as a negative feedback mechanism to restrict Cdx1 expression to the caudal embryo.