NORMAL DEVELOPMENT AND GROWTH OF MICE CARRYING A TARGETED DISRUPTION OF THE ALPHA-1 RETINOIC ACID RECEPTOR GENE

Three unlinked genes encode receptors for retinoic acid (RARalpha, -beta, and -gamma). Each gene expresses two major protein isoforms differing in the amino terminal A domain by alternative promoter use, fused to common exons encoding most of the receptor protein. The two RARalpha transcripts (RARalpha1 and -alpha2) are differentially expressed and evolutionarily conserved, as are the RARbeta and -gamma transcripts, suggesting that each isoform may have specific functions in the development of animals. To address the biological function of the alpha1 receptor, we have disrupted the portion of the RARalpha gene encoding this isoform by homologous recombination in mouse embryonic stem cells. Surprisingly, offspring homozygous for this mutation were viable and showed no apparently altered phenotype. RNA analysis confirmed that the RARalpha1 transcript was absent in homozygous tissues, and no evidence for a compensatory increase of RARalpha2 or of another RAR gene was obtained to account for the vitality of the mutant animals. These results clearly demonstrate that loss of RARalpha1 function does not disrupt embryonic development and argue for combinatorial or overlapping functions among the RAR isoforms.