DEVELOPMENTAL ROLES OF THE RETINOIC ACID RECEPTORS

Retinoic acid, one of the principle active metabolites of vitamin A (r etinol), is believed to be essential for numerous developmental and ph ysiological processes. Vitamin A deprivation (VAD) during development leads to numerous congenital defects. Previous studies of retinoic aci d receptor (RAR) deficient mice failed to reveal any of these VAD-indu ced defects. This finding suggested that either the RARs are functiona lly redundant or that they are not critically required during developm ent. In order to address these possibilities, we derived a number of R AR compound mutants. Unlike RAR single mutants, these compound null mu tants died either in utero or shortly following birth. Histological an alysis revealed essentially all of the defects characteristic of fetal VAD. A number of additional malformations, not described in previous VAD studies, were also observed. These included defects of the ocular and salivary glands and their ducts, the skeletal elements of the fore - and hindlimbs, and the cervical region of the axial skeleton. In add ition, with the exception of derivatives forming within the first phar yngeal arch, most of the elements derived from mesectoderm emanating f rom cranial and hindbrain levels were affected. A number of these muta nts also exhibited supernumerary cranial skeletal elements characteris tics of the reptilian skull. A summary of the defects found in these R AR double mutants is presented.