Grb7,Grb10andGrb14,encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism

Abstract

BackgroundThe growth factor receptor bound 7 (Grb7) family of signalling adaptor proteins comprises Grb7, Grb10 and Grb14. Each can interact with the insulin receptor and other receptor tyrosine kinases, where Grb10 and Grb14 inhibit insulin receptor activity. In cell culture studies they mediate functions including cell survival, proliferation, and migration. Mouse knockout (KO) studies have revealed physiological roles forGrb10andGrb14in glucose-regulated energy homeostasis. BothGrb10KO andGrb14KO mice exhibit increased insulin signalling in peripheral tissues, with increased glucose and insulin sensitivity and a modestly increased ability to clear a glucose load. In addition,Grb10strongly inhibits fetal growth such that at birthGrb10KO mice are 30% larger by weight than wild type littermates.ResultsHere, we generate aGrb7KO mouse model. We show that during fetal development the expression patterns of Grb7 and Grb14 each overlap with that of Grb10. Despite this,Grb7andGrb14did not have a major role in influencing fetal growth, either alone or in combination withGrb10. At birth, in most respects bothGrb7KO andGrb14KO single mutants were indistinguishable from wild type, whileGrb7:Grb10double knockout (DKO) were near identical toGrb10KO single mutant andGrb10:Grb14DKO mutants slightly smaller. In the developing kidneyGrb7had a subtle positive influence on growth. An initial characterisation ofGrb7KO adult mice revealed sexually dimorphic effects on energy homeostasis, with females having significantly smaller white adipose tissue (WAT) depots and an enhanced ability to clear glucose from the circulation, compared to wild type littermates. Males had elevated fasted glucose levels with a trend towards smaller WAT depots, without improved glucose clearance.ConclusionsGrb7andGrb14do not have significant roles as inhibitors of fetal growth, unlikeGrb10, and insteadGrb7may promote growth of the developing kidney. In adulthood,Grb7contributes subtly to glucose mediated energy homeostasis, raising the possibility of redundancy between all three adaptors in physiological regulation of insulin signalling and glucose handling.