Limited specificity and large overlap of the functions of the mouse RARγ1 and RARγ2 isoforms

The RARy gene generates two major isoforms, RARyl and RARy2, which originate from two distinct promoters. We report here the engineering of mice lacking RARyl, but in which RARy2 is normally expressed. The effect of this null mutation has been compared with those previously described for RARy2 and all RARy isoforms (total RARy gene inactivation), both in single mutants and in double mutants bearing additional null mutations in their RARa, RAR/3 or RXRCX genes. RARyl mutants, but not RARy2 mutants, displayed a subset of the abnormalities exhibited by total RARy null mutants (growth deficiency, abnormal cricoid cartilage and occasional cervical vertebra defects), suggesting that RARyl is the main isoform mediating the corresponding RARy functions. Interestingly, cricoid cartilage defects were also found in a fraction of heterozygote animals for the RARyl, RARy or RARa mutations, indicating that wild type levels of RARs are required for the normal morphogenesis of this structure. Compound RARcu/RARyl and RARtiARy2 double null mutants exhibited only a small fraction of the defects found in RAR&RARy double null mutants. Moreover, these defects were often partially penetrant, or corresponded to a less severe form. However, they occurred preferentially in certain compound mutants, demonstrating that given isoforms mediate specific functions of RARy in the context of a RARol null background. In a RXRor null background, both RARyl and y2 isoform mutations resulted in increased severity of the RXRo( null ocular phenotype. Together, the present observations indicate that the functions of the two RARy isoforms overlap to a large extent, but also that each of these isoforms exhibits a limited functional specificity. Furthermore, the occurrence of morphological defects in heterozygote mutants for a single RAR isoform provides a basis for explaining the strong conservation of these isoforms during vertebrate evolution.