RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis.

Abstract

We have established a targeted loss-of-function mutation in the RXR~ gene in the mouse germ line that results in embryonic lethality between E13.5 and E16.5 when bred to homozygosity. The major defect responsible for lethality is hypoplastic development of the ventricular chambers of the heart, which is manifest as a grossly thinned ventricular wall with concurrent defects in ventricular septation. This phenotype is identical to a subset of the effects of embryonic vitamin A deficiency and, therefore, establishes RXR~ as a genetic component of the vitamin A signaling pathway in cardiac morphogenesis. The cardiac outflow tracts and associated vessels, which are populated by derivatives of the neural crest and which are also sensitive to vitamin A deficiency, are normal in homozygous embryos, indicating the genetic independence of ventricular chamber development. Hepatic differentiation was dramatically but transiently retarded yet is histologically and morphologically normal. These results ascribe an essential function for the RXR,~ gene in embryonic development and provide the first evidence of a requirement for RXR in one of its predicted hormone response pathways.

PDGF‐A as an epicardial mitogen during heart development

“…RA is made by embryonic epicardium and by EMC cells, and we have proposed that RA signaling in vivo is required for the production of epicardial mitogens. Thus, mouse embryos lacking the RA receptor RXR␣ show a profoundly hypoplastic ventricular chamber wall (Sucov et al, 1994), and this phenotype is replicated (albeit to a less severe extent) in epicardium-specific RXR␣ mutants (Merki et al, 2005). With the identification of PDGF-A as a mitogen made by EMC cells, we addressed the potential role of RA in Pdgfa expression or PDGF-A secretion.…”

Functional specificity of the two retinoic acid receptor RAR and RXR families in myogenesis

“…This is supported by the presence of retinoids in myogenic precursor cells (Wagner et al, 1990(Wagner et al, , 1992Chen et al, 1992) and RA-receptors in muscle tissue Dolle et al, 1994;GigueÁ re, 1994). However, the knock-outs of RARs and RXRs in the mouse to date did not compromise skeletal muscle development (Kastner et al, , 1996bSucov et al, 1994;Lohnes et al, 1995;Krezel et al, 1996) probably due to a large degree of functional redundancy among these receptors which prevented a de®nitive assignment of their physiological functions in the animal. To disable completely the retinoid pathway in skeletal muscle, it will be necessary to generate multiple knock-outs of RARs and RXRs.…”

Oligo-astheno-teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta

“…Although the RXR family members Rxra, Rxrb and Rxrg share structural similarities, genetic analyses suggest that each has distinct roles in mice [24][25][26] . Our data show that testicular phenotypes of male Cnot7 -/-mice are similar to those of Rxrb -/-mice (vacuole formation, failure in alignment of late spermatids, multiple generations of spermatids, lipid accumulation in the cytoplasm of Sertoli cells and no apparent phenotypic abnormalities in other adult tissues), suggesting that Cnot7 functionally interacts with Rxrb but not with other family members.…”