Retinoic acid receptor β2 (RARβ2) null mutantmice appear normal

Abstract

Vertebrates are highly sensitive to bothretinoic acid (RA) deficiency and excess. The RA signal is thought to be transduced by nuclear receptors (the RAR and RXR families) which activate the expression of target genes via cis-acting transcriptional enhancer elements. Each of the threeRAR genes, RARα, RARβ, and RARγ, gives rise to several isoforms by differential usage of two promoters and alternative splicing. RARβ2 is the most abundant of the four RARβ isoforms, and its transcription is spatially and temporally restricted in developing embryos, suggesting that it might perform specificfunctions. Furthermore, RARβ2 expression can be induced via a retinoic acid response element located in its promoter region. This RA effect is particularly interesting since under conditions of RA excess, RARβ2 promoter activity and transcript accumulation are induced in regions of developing embryos in which malformations subsequently appear, such as the craniofacial region, the hindbrain, and the limbs. These findings haveled to the suggestion that the RARβ2 isoform might mediate some of the teratogenic effects of RA. In this study, we have eliminated RARβ2 expression by targeted gene disruption. RARβ2 null mutants exhibit an apparently normal phenotype, indicating that other RARs must compensate for RARβ2 sufficiently well to allow normal prenatal and postnatal development to proceed. By challenging RARβ2 null embryos with teratogenic doses of RA, we have also directly addressed the question of whether RARβ2 is required for mediating RA-induced malformations. © 1994 by Academic Press, Inc.