Imprinted genes and placental growth: Implications for the developmental origins of health and disease

Introduction: The discovery in 1991 that a growth factor gene, Igf2, and the gene encoding its antagonistic clearance receptor, Igf2r, are expressed monoallelically from opposite parental alleles in mice owing to parental imprinting, initiated a burst of research activity which has by now largely defined the repertoire of imprinted genes. Since 2006, when we last reviewed this area, progress has continued, with established laboratories filling in key experimental gaps and new investigators entering the field. Here we provide an updated overview of this area and propose some lines of investigation that seem particularly compelling for future work. Given that an important group of imprinted genes have been shown to act as rheostats for placental growth, we consider whether mice engineered to over- and underexpress specific imprinted genes in the placenta might be developed as experimental models for exploring the developmental origins of health and disease (DOHAD) hypothesis. Such models could become useful for testing interventions to ameliorate the adverse cardiovascular, metabolic and psychological effects in adults that can result from a poor in utero environment. We illustrate this direction of work with our studies of the imprinted Phlda2 gene, which regulates placental and, secondarily, fetal growth in mouse models and appears likely to have these same functions in human pregnancies.