Compound mutants for retinoic acid receptor (RAR)β and RARα1 reveal developmental functions for multiple RARβ isoforms

Abstract Mice with targeted disruptions in retinoic acid receptor genes have been generated to assess the role of nuclear receptors as transducers of the retinoid signal during vertebrate development. Mice with mutations that disrupt all isoforms of the RARα, RARβ and RARγ genes as well as for the individual RARα1, RARβ2 and RARγ2 have been described. By breeding the RARα1 and RARβ strains together we have generated double mutants which have striking phenotypes not discernible in mice homozygous for the individual mutations. Mice lacking both RARα1 and RARβ died shortly after birth because of hypoxia, although individual RARα1 and RARβ mutants were phenotypically normal. As previously observed in RAR compound mutants, histological examination of 18.5 dpc fetuses of RARα1 −/− β −/− double mutants revealed a number of congenital malformations which in many respects were similar to those observed in fetuses of vitamin A-deficient mothers. The regions of congenital defects in RARα1 −/− β −/− double mutants included the eye, the skull, the respiratory tract, the heart, the aortic arch-derived great vessels, and urogenital system. The penetrance of malformations in RARα1 −/− β −/− mutants was greater than that in the reported RARα1 −/− β2 −/− double mutants. Moreover, RARα1 −/#x02212; β −/− mutants exhibited hypoplastic lungs and ossified fusion between basioccipital and exoccipital bones that were not reported in the RARα1 −/− β2 −/Ȓ animals, and displayed ectopic thymus and an unique defect in testis suggesting specific roles for RARβ1, 3 and/or 4 isoforms in these structures. The RARα1 single mutant animals as well as RARα1 −/− β −/− double mutant mice were susceptible to the teratogenic effects of RA, demonstrating that RARα1 and RARβ isoforms singly or in combination do not play a major role in RA-induced craniofacial malformation and limb deformities.