Embryonic Expression of NrasG 12 D Leads to Embryonic Lethality and Cardiac Defects

Ras proteins control a complex intracellular signaling network. Gain-of-function mutations in RAS genes lead to RASopathy disorders in humans, including Noonan syndrome (NS). NS is the second most common syndromic cause of congenital heart disease. Although conditional expression of the Nras(G12D/)(+) mutation in adult hematopoietic system is leukemogenic, its effects on embryonic development remain unclear. Here, we report that pan-embryonic expression of endogenous Nras(G12D/)(+) by Mox2-Cre in mice caused embryonic lethality from embryonic day (E) 15.5 and developmental defects predominantly in the heart. At E13.5, Nras(G12D/)(+); Mox2(Cre/)(+) embryos displayed a moderate expansion of hematopoietic stem and progenitor cells without a significant impact on erythroid differentiation in the fetal liver. Importantly, the mutant embryos exhibited cardiac malformations resembling human congenital cardiac defects seen in NS patients, including ventricular septal defects, double outlet right ventricle, the hypertrabeculation/thin myocardium, and pulmonary valve stenosis. The mutant heart showed dysregulation of ERK, BMP, and Wnt pathways, crucial signaling pathways for cardiac development. Endothelial/endocardial-specific expression of Nras(G12D/)(+) caused the cardiac morphological defects and embryonic lethality as observed in Nras(G12D/)(+); Mox2(Cre/)(+) mutants, but myocardial-specific expression of Nras(G12D/)(+) did not. Thus, oncogenic Nras(G12D) mutation may not be compatible with embryonic survival.

Automated summary

Ras proteins play a crucial role in controlling intracellular signaling networks, and gain-of-function mutations in RAS genes can lead to embryonic lethality and cardiac developmental defects in mice similar to those seen in patients with NS.