Key result
Double knock-out of IP3R1 and IP3R2 in mice resulted in embryonic lethality by day 11.5 with severe developmental defects in the ventricular myocardium and atrioventricular canal.
IP3R1 and IP3R2 are essential for normal cardiogenesis and embryonic survival, functioning in part through the regulation of calcineurin-NFAT signaling.
IP3R1/IP3R2 essentiality in mouse cardiogenesis leaves open their contribution to human congenital heart defects pending further models.
BACKGROUND: Inositol 1,4,5-trisphosphate receptors (IP3R1, 2, and 3) are intracellular Ca2+ release channels that regulate various vital processes. Although the ryanodine receptor type 2, another type of intracellular Ca2+ release channel, has been shown to play a role in embryonic cardiomyocytes, the functions of the IP3Rs in cardiogenesis remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: We found that IP3R1(-/-)-IP3R2(-/-) double-mutant mice died in utero with developmental defects of the ventricular myocardium and atrioventricular (AV) canal of the heart by embryonic day (E) 11.5, even though no cardiac defect was detectable in IP3R1(-/-) or IP3R2(-/-) single-mutant mice at this developmental stage. The double-mutant phenotype resembled that of mice deficient for calcineurin/NFATc signaling, and NFATc was inactive in embryonic hearts from the double knockout-mutant mice. The double mutation of IP3R1/R2 and pharmacologic inhibition of IP3Rs mimicked the phenotype of the AV valve defect that result from the inhibition of calcineurin, and it could be rescued by constitutively active calcineurin. CONCLUSIONS/SIGNIFICANCE: Our results suggest an essential role for IP3Rs in cardiogenesis in part through the regulation of calcineurin-NFAT signaling.
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Uchida et al. (2010) studied Cardiogenesis and embryonic heart development. IP3R1 and IP3R2 double gene knock-out vs. Wild-type or single-mutant embryos was evaluated on Embryonic survival and cardiac morphological development. Double knock-out of IP3R1 and IP3R2 in mice resulted in embryonic lethality by day 11.5 with severe developmental defects in the ventricular myocardium and atrioventricular canal.