TY - JOUR
T1 - Developmental Programming Mediated by Complementary Roles of Imprinted Grb10 in Mother and Pup
AU - Cowley, Michael
AU - Garfield, Alastair S.
AU - Madon-Simon, Marta
AU - Charalambous, Marika
AU - Clarkson, Richard W.
AU - Smalley, Matthew J.
AU - Kendrick, Howard
AU - Isles, Anthony R.
AU - Parry, Aled J.
AU - Carney, Sara
AU - Oakey, Rebecca J.
AU - Heisler, Lora K.
AU - Moorwood, Kim
AU - Wolf, Jason B.
AU - Ward, Andrew
N1 - Funding: We acknowledge funding from the Wellcome Trust and Medical Research Council UK (A. Ward); a University of Bath scholarship and a King's College London/The London Law Trust Medal Fellowship to M. Cowley; Cardiff University, Cancer Research UK and Breast Cancer Campaign (M.J. Smalley); a Medical Research Council scholarship (to A.S. Garfield); a University of Bath scholarship (to M. Madon-Simon); and a Wellcome Trust grant (085448/Z/08/Z) (to R.J. Oakey). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2014/2/25
Y1 - 2014/2/25
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pbio.1001799
DO - 10.1371/journal.pbio.1001799
M3 - Article
SN - 1544-9173
VL - 12
JO - PLoS Biology
JF - PLoS Biology
IS - 2
M1 - 1001799
ER -
