ImprintedGrb10, encoding growth factor receptor bound protein 10, regulates fetal growth independently of the insulin-like growth factor type 1 receptor (Igf1r) and insulin receptor (Insr) genes

Abstract

AbstractBackgroundOptimal size at birth dictates perinatal survival and long-term risk of developing common disorders such as obesity, type 2 diabetes and cardiovascular disease. The imprintedGrb10gene encodes a signalling adaptor protein capable of inhibiting receptor tyrosine kinases, including the insulin receptor (Insr) and insulin-like growth factor type 1 receptor (Igf1r).Grb10restricts fetal growth such thatGrb10knockout (KO) mice are at birth some 25-35% larger than wild type. Using a mouse genetic approach, we test the widely held assumption that Grb10 influences growth through interaction with Igf1r, which has a highly conserved growth promoting role.ResultsShould Grb10 interact with Igf1r to regulate growthGrb10:Igf1rdouble mutant mice should be indistinguishable fromIgf1rKO single mutants, which are around half normal size at birth. Instead,Grb10:Igf1rdouble mutants were intermediate in size betweenGrb10KO andIgf1rKO single mutants, indicating additive effects of the two signalling proteins having opposite actions in separate pathways. Some organs examined followed a similar pattern, thoughGrb10KO neonates exhibited sparing of the brain and kidneys, whereas the influence ofIgf1rextended to all organs. An interaction between Grb10 and Insr was similarly investigated. While there was no general evidence for a major interaction for fetal growth regulation, the liver was an exception. The liver inGrb10KO mutants was disproportionately overgrown with evidence of excess lipid storage in hepatocytes, whereasGrb10:Insrdouble mutants were indistinguishable fromInsrsingle mutants or wild types.ConclusionsGrb10 acts largely independently of Igf1r or Insr to control fetal growth and has a more variable influence on individual organs. Only the disproportionate overgrowth and excess lipid storage seen in theGrb10KO neonatal liver can be explained through an interaction between Grb10 and the Insr. Our findings are important for understanding how positive and negative influences on fetal growth dictate size and tissue proportions at birth.