LAUSR

The process of cardiogenesis is very complex, requiring cells derived from at least four distinct progenitor populations, an elaborate transcriptional network, and the integration of many different signalling pathways. A failure of any of the individual elements can result in a variety of types of heart defects. In humans, such heart defects are called congenital heart disease (CHD), and this is the most common type of human birth defect, being present in ~1% of live births and ~10% of still-births worldwide. However, despite intensive investigation by classical and next-generation genetic and genomic methods, currently only about one-fifth of cases can be explained genetically. This is because CHD can also be caused by non-genetic factors, for example by environmental stresses during pregnancy. Such factors identified using epidemiology or animal studies include maternal conditions and diseases like viral infection and hyperthermia, folate deficiency, hypertension, stress, pre-existing diabetes and phenylketonuria. In addition, maternal exposures to pharmaceuticals such as anti-convulsant and anti-arrhythmia ionchannel blockers, anti-depressants, retinoic acid, thalidomide or environmental pollutants have also been associated with increased CHD risk. However, despite these factors being known for many decades, virtually nothing is known of how they cause CHD. We are studying mouse models of several such environmental factors to elucidate the molecular mechanisms by which these factors perturb embryonic cardiogenesis.