Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse

Retinoic acid (RA), the active derivative of vitamin A, has been implicated in various steps of cardiovascular development, but its contribution to ea rly heart morphogenesis has not been clearly established in a mammalian sys tem, To block endogenous RA synthesis, we have disrupted the gene encoding RALDH2, the first retinaldehyde dehydrogenase whose expression has been det ected during early mouse post-implantation development. We describe here th e heart abnormalities of the RA-deficient Raldh2 mutants that die in utero at gestational day 10.5. The embryonic heart tube forms properly, but fails to undergo rightward looping and, instead, forms a medial distended cavity , Expression of early heart determination factors is not altered in mutants , and the defect in heart looping does not appear to involve the Nodal/Left y/Pitx2 pathway. Histological and molecular analysis reveal distinct antero posterior components in the mutant heart tube, although posterior chamber ( atria and sinus venosus) development is severely impaired. Instead of formi ng trabeculae, the developing ventricular myocardium consists of a thick la yer of loosely attached cells. Ultrastructural analysis shows that most of the ventricular wall consists of prematurely differentiated cardiomyocytes, whereas undifferentiated cells remain clustered rostrally. We conclude tha t embryonic RA synthesis is required for realization of heart looping, deve lopment of posterior chambers and proper differentiation of ventricular car diomyocytes, Nevertheless, the precise location of this synthesis may not b e crucial, as these defects can mostly be rescued by systemic (maternal) RA administration. However, cardiac neural crest cells cannot be properly res cued in Raldh2(-/-) embryos, leading to outflow tract septation defects.