RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis.
We have established a targeted loss-of-function mutation in the RXR alpha 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 alpha 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 alpha gene in embryonic development and provide the first evidence of a requirement for RXR in one of its predicted hormone response pathways.
Sucov
H M
HM
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92138.
Dyson
E
E
Gumeringer
C L
CL
Price
J
J
Chien
K R
KR
Evans
R M
RM
D000818:Animals; D005314:Embryonic and Fetal Development; D005260:Female; D005318:Fetal Heart / Q000196:embryology*; D018390:Gene Targeting; D018095:Germ-Line Mutation; D006352:Heart Ventricles / Q000196:embryology; D006720:Homozygote; D008099:Liver / Q000196:embryology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000502:physiology; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D015398:Signal Transduction; D014157:Transcription Factors; D014801:Vitamin A / Q000502:physiology*
D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014801:Vitamin A