Congenital heart disease (CHD) is the most common form of human birth defect, yet the genetic and environmental factors that contribute to CHD remain poorly understood. Here, Sally Dunwoodie and colleagues investigate how gestational hypoxia affects heart development in mouse embryos (p. ) They reveal that the exposure of developing mouse embryos to short-term hypoxia in utero results in heart defects, notably perturbations to the outflow tract (OFT). These changes are mediated by altered cell proliferation and FGF signalling in the secondary heart field (SHF), which contains progenitor cells that contribute to the OFT. The authors further report that hypoxia leads to rapid induction of the unfolded protein response (UPR) in SHF cells. This, in turn, causes a global decrease in protein translation and may contribute to the reduced levels of FGFR1, and hence FGF signalling, observed in SHF cells following exposure to hypoxia. Together, these results suggest that hypoxia-mediated UPR induction during pregnancy can give rise to CHD. Given the key role of FGF signalling during embryogenesis, these findings also have important implications for understanding birth defects that affect other organs.
