Investigating how genetic and environmental factors disrupt mammalian embryogenesis
Victor Chang Cardiac Research Institute, Sydney, Australia.
Congenital malformations arise due to genetic and environmental factors and understanding the interplay between these in causing malformation might lead to preventative opportunities, in some cases. We are identifying genetic and environmental factor that disrupt embryogenesis in human and mouse. In mice, we have shown that short-term gestational hypoxia disrupts progenitor cell populations in embryos, leading to vertebral and cardiac defects that are commonly found in humans. We showed that hypoxia induced the unfolded protein response (UPR) and in doing so inhibited cap-dependent translation, which resulted in the loss of fibroblast growth factor signal transduction in progenitor cells in the presomitic mesoderm and the second heart field. We propose that many environmental risk factors for congenital malformation in humans induce the UPR and that this might be a unifying mechanism leading to disrupted embryogenesis (Sparrow et al Cell 2012; Shi et al Development 2016). In humans studying families with vertebral and cardiac defects we identified mutations in four cases in either of two genes: 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU), encoding kynurenine pathway enzymes. All four patients had vertebral, cardiac and renal defects, amongst others and recurrent miscarriage was a feature in two families. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan via the kynurenine pathway. NAD is also synthesized more directly from vitamin B3. The patients had reduced circulating NAD levels. Haao or Kynu null mouse embryos developed similar defects to the patients, due to NAD deficiency. In null mice NAD deficiency, malformations and miscarriage were prevented by niacin (vitamin B3) supplementation during gestation (Shi et al NEJM 2017).