Developmental Programming Mediated by Complementary Roles of Imprinted Grb10 in Mother and Pup

Developmental programming links growth in early life with health status in adulthood. Although environmental factors such as maternal diet can influence the growth and adult health status of offspring, the genetic influences on this process are poorly understood. Using the mouse as a model, we identify the imprinted gene Grb10 as a mediator of nutrient supply and demand in the postnatal period. The combined actions of Grb10 expressed in the mother, controlling supply, and Grb10 expressed in the offspring, controlling demand, jointly regulate offspring growth. Furthermore, Grb10 determines the proportions of lean and fat tissue during development, thereby influencing energy homeostasis in the adult. Most strikingly, we show that the development of normal lean/fat proportions depends on the combined effects of Grb10 expressed in the mother, which has the greater effect on offspring adiposity, and Grb10 expressed in the offspring, which influences lean mass. These distinct functions of Grb10 in mother and pup act complementarily, which is consistent with a coadaptation model of imprinting evolution, a model predicted but for which there is limited experimental evidence. In addition, our findings identify Grb10 as a key genetic component of developmental programming, and highlight the need for a better understanding of mother-offspring interactions at the genetic level in predicting adult disease risk. Author Summary Experiences during early life can impact on health status in adulthood; low birth weight, for example, is linked to an increased risk of diabetes and obesity in later life. Such developmental programming can be influenced by environmental factors such as diet, but the importance of genetics in this process is not well understood. Using the mouse as a model, we investigate the gene Grb10, which is imprinted, meaning that it is expressed from only one of its two copies. We show that Grb10 is a key mediator of developmental programming, controlling supply and demand of nutrients in the postnatal period and influencing growth and body composition. Specifically, we find that Grb10 determines the proportions of lean and fat tissue during development, and that this is dependent on the combined actions of Grb10 in the mother and offspring. Our findings have two main implications. First, they suggest that the functions of Grb10 in mother and offspring are coadapted, providing support for a coadaptation model for the evolution of imprinted genes. Second, they highlight the need for a better grasp of how maternal and offspring genetics interact during development if we are to understand more fully the causes of complex adult disorders such as obesity.