Inositol 1,4,5-trisphosphate receptors are essential for the development of the second heart field

Congenital heart defects (CHDs) occur in 0.5–1% of live births, yet the underlying genetic etiology remains mostly unknown. Recently, a new source of myocardial cells, namely the second heart field (SHF), was discovered in the splanchnic mesoderm. Abnormal development of the SHF leads to a spectrum of outflow tract defects, such as persistent truncus arteriosus and tetralogy of Fallot. Intracellular Ca2+ signaling is known to be essential for many aspects of heart biology including heart development, but its role in the SHF is uncertain. Here, we analyzed mice deficient for genes encoding inositol 1,4,5-trisphosphate receptors (IP3Rs), which are intracellular Ca2+ release channels on the endo/sarcoplasmic reticulum that mediate Ca2+ mobilization. Mouse embryos that are double mutant for IP3R type 1 and type 3 (IP3R1−/−IP3R3−/−) show hypoplasia of the outflow tract and the right ventricle, reduced expression of specific molecular markers and enhanced apoptosis of mesodermal cells in the SHF. Gene expression analyses suggest that IP3R-mediated Ca2+ signaling may involve, at least in part, the Mef2C–Smyd1 pathway, a transcriptional cascade essential for the SHF. These data reveal that IP3R type 1 and type 3 may play a redundant role in the development of the SHF.

Research highlights
► IP3R1/3 double deficiency leads to hypoplasia of the outflow region in fetal heart.
► IP3R1/3 double deficiency results in decreased expression domain of Bmp4 and Isl1.
► IP3R1/3 double deficiency increases apoptosis in the second heart field.
► IP3R1/3 double deficiency leads to downregulation of Mef2c and Smyd1.
► IP3R1/3 are redundantly essential for the development of the second heart field.