Mice lacking all isoforms of retinoic acid receptor β develop normally and are susceptible to the teratogenic effects of retinoic acid

Abstract

Retinoic acids (RA) are vitamin A derivatives essential for normal embryonic development and viability of vertebrates. The RA signal is mediated by two distinct classes of receptors, RA receptors (RARs) and retinoid X receptors (RXRs). The RAR family is composed of three genes: RAR alpha, beta, and gamma. The expression of RAR beta gene is spatially and temporally restricted in certain structures in the developing embryo, suggesting that RAR beta could play specific roles during morphogenesis. Four isoforms of the RAR beta gene (beta 1-beta 4) are generated by differential usage of promoters and alternative splicing. It has recently been demonstrated that the RAR beta 2 isoform is dispensable for normal development. To ascertain the function of all RAR beta isoforms in vivo, we have generated a mutation that disrupts all isoforms of the RAR beta gene in the mouse by gene targeting in embryonic stem cells. Mice homozygous for the mutation are viable and fertile with no externally apparent abnormalities. During development, 1/11 RAR beta mutant embryos showed fusion of the ninth and tenth cranial ganglia on both sides of the hindbrain. However, no obvious alterations in the spatial pattern of expression of Hoxb-1, Hoxb-4 and Hoxb-5 were observed in day 9.5 p.c. embryos. The RAR beta null mutation did not alter the pattern or extent of the limb and craniofacial malformations induced by RA excess, suggesting that RAR beta may not be mandatory to mediate the observed teratological effects of RA in these structures. These experiments demonstrate that RAR beta isoforms are not absolutely required for embryonic development and provide additional support to the concept of functional redundancy among members of the RAR family.

Stromal retinoic acid receptor β promotes mammary gland tumorigenesis

“…1 A and B). As could be expected, this delay was transient, because mammary tree outgrowth was found to be normal, and the gland was fully functional at later stages of development, as previously observed (33). Because of the important role played by the stroma in all stages of mammary gland development (34), we next profiled the transcriptome of mammary stroma isolated from 40-d-old wild-type and Rarb −/− females.…”

Retinoid-induced apoptosis in normal and neoplastic tissues

“…Deletion of individual RARs in mice by homologous recombination (receptor knock-outs) have produced surprisingly modest phenotypic consequences. The RARb-null genotype is without an apparent phenotype (Luo et al, 1995). The knock-out of RARa1, the predominant RARa isoform in the embryo, has no discernable phenotype (Li et al, 1993;Lufkin et al, 1993).…”

Thyroid hormone actions on cartilage and bone: interactions with other hormones at the epiphyseal plate and effects on linear growth

“…Retinoids are potent teratogens that cause intrauterine abnormalities of limb formation and promote epiphyseal plate closure in animal studies (Standeven et al 1996). Expression of retinoid receptors has been widely documented in developing cartilage and their ontogeny has been implicated in control of endochondral bone formation during mouse embryogenesis (Noji et al 1989, Dolle et al 1990, Ruberte et al 1990, Mendelsohn et al 1991, Lohnes et al 1993, Luo et al 1995, Sucov et al 1995. The major effects of retinoids on skeletal formation occur during chondrogenesis, and RAR is required for initiation of chondrocyte differentiation (Cash et al 1997).…”