Sphingosine 1-phosphate receptor-1 in cardiomyocytes is required for normal cardiac development

Sphingosine 1-phosphate (S1P) is a bioactive lipid that acts via G protein-coupled receptors. The S1P receptor S1P1, encoded by S1pr1, is expressed in developing heart but its roles there remain largely unexplored. Analysis of S1pr1 LacZ knockin embryos revealed β-galactosidase staining in cardiomyocytes in the septum and in the trabecular layer of hearts collected at 12.5 days post coitus (dpc) and weak staining in the inner aspect of the compact layer at 15.5 dpc and later. Nkx2-5-Cre- and Mlc2a-Cre-mediated conditional knockout of S1pr1 led to ventricular noncompaction and ventricular septal defects at 18.5 dpc and to perinatal lethality in the majority of mutants. Further analysis of Mlc2a-Cre conditional mutants revealed no gross phenotype at 12.5 dpc but absence of the normal increase in the number of cardiomyocytes and the thickness of the compact layer at 13.5 dpc and after. Consistent with relative lack of a compact layer, in situ hybridization at 13.5 dpc revealed expression of trabecular markers extending almost to the epicardium in mutants. Mutant hearts also showed decreased myofibril organization in the compact but not trabecular myocardium at 12.5 dpc. These results suggest that S1P signaling via S1P1 in cardiomyocytes plays a previously unknown and necessary role in heart development in mice.