Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development.
We describe here the analysis of congenital malformations in compound mutant fetuses bearing null alleles in one RXR (alpha, beta or gamma) and one RAR (alpha, beta or gamma) isotype gene. A marked synergy was observed between the effects of mutations in RXR alpha and RARs, as a large number of developmental defects previously found mainly in RAR single and compound mutants were recapitulated in specific RXR alpha/RAR compound mutants. Several malformations were seen only in one type of RXR alpha/RAR mutant combination, whereas others were seen in several types of RXR alpha/RAR double mutants. No synergy was observed between the effects of mutations of either RXR beta or RXR gamma mutations and those of any of the RAR mutations. These genetic data suggest that RXR/RAR heterodimers are the functional units transducing the retinoid signal for a large number of RA-dependent processes, and furthermore, that RXR alpha is the main RXR implicated in the developmental functions of RARs. The significance of these observations is discussed with respect to the problem of functional specificity and redundancy among retinoid receptors in vivo.
Kastner
P
P
Institut de Géńetique et de Biologie Moléculaire et Cellulaire, CNRS-INSERM-ULP-Collège de France, Illkirch, France.
Mark
M
M
Ghyselinck
N
N
Krezel
W
W
Dupé
V
V
Grondona
J M
JM
Chambon
P
P
D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics*; D000818:Animals; D002874:Chromosome Mapping; D019281:Dimerization; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008817:Mice, Mutant Strains; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D000097768:Retinoic Acid Receptor gamma
D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors; D000097768:Retinoic Acid Receptor gamma; C000607072:Rara protein, mouse; C082925:retinoic acid receptor beta