ATRIAL-LIKE PHENOTYPE IS ASSOCIATED WITH EMBRYONIC VENTRICULAR FAILURE IN RETINOID-X RECEPTOR-ALPHA - --MICE/

We have recently characterized a cardiac model of ventricular chamber defects in retinoid X receptor a (RXR alpha) homozygous mutant (-/-) g ene-targeted mice, These mice display generalized edema, ventricular c hamber hypoplasia, and muscular septal defects, and they die at embryo nic day 15. To substantiate our hypothesis that the embryos are dying of cardiac pump failure, we have used digital bright-field and fluores cent video microscopy and in vivo microinjection of fluorescein-labele d albumin to analyze cardiac function. The affected embryos showed dep ressed ventricular function (average left ventricular area ejection fr action, 14%), ventricular septal defects, and various degrees of atrio ventricular block not seen in the RXR alpha wild-type (+/+) and hetero zygous (+/-) littermates (average left ventricular area ejection fract ion, 50%). The molecular mechanisms involved in these ventricular defe cts were studied by evaluating expression of cardiac-specific genes kn own to be developmentally regulated. By in situ hybridization, aberran t, persistent expression of the atrial isoform of myosin Light chain 2 was identified in the ventricles, We hypothesize that retinoic acid p rovides a critical signal mediated through the RXR alpha pathway that is required to allow progression of development of the ventricular reg ion of the heart from its early atrial-like form to the thick-walled a dult ventricle. The conduction system disturbances found in the RXR al pha -/- embryos may reflect a requirement of the developing conduction system for the RXR alpha signaling pathway, or it may be secondary to the failure of septal development.