GENETIC-ANALYSIS OF RXR-ALPHA, DEVELOPMENTAL FUNCTION - CONVERGENCE OF RXR AND RAR SIGNALING PATHWAYS IN HEART AND EYE MORPHOGENESIS

A null mutation was generated in the mouse RXR alpha gene by targeted disruption. Growth deficiency occurred in heterozygote mice. Null muta nts died in utero and displayed myocardial and ocular malformations. T hese malformations belong to the fetal vitamin A deficiency syndrome, supporting the idea that RXR alpha is involved in retinoid signaling i n vivo. A phenotypic synergy was observed when the RXR alpha mutation was introduced into RAR alpha or RAR gamma mutant backgrounds: RXR alp ha null mutants and RXR alpha(+/-)/RAR gamma(-/-) double mutants displ ayed similar ocular defects, which became more severe in RXR alpha(-/- )/RAR gamma(+/-) and RXR alpha(-/-)/RAR gamma(-/-) mutants. Furthermor e, RXR alpha/RAR double mutants exhibited several malformations not se en in single mutants. This functional convergence strongly suggests th at RXR alpha/RAR heterodimers mediate retinoid signaling in vivo.