LAUSR

environmental factor present during embryonic heart develop can also cause CHD. Here we propose a plausible non-genetic mechanism for induction of CHD by hypoxia, a common environmental stressor. We present evidence that short-term gestational hypoxia can perturb mammalian heart formation, resulting in defects of outflow tract alignment and/or elongation. We show that hypoxic exposure results in reduced cellular proliferation in the second heart field (SHF) and elsewhere. In the SHF this is likely to bedue to a downregulation of FGF signaling,mediated by the specific loss of the receptor FGFR1. We show that hypoxia induces the unfolded protein response (UPR), causing a global downregulation of protein translation. Our findings have far-reaching consequences because the UPR is activated by amyriad of environmental or pathophysiological conditions. Ultimately, this enables a better understanding of the mechanisms involved in the origins of sporadic CHD in humans.