Rescue of Growth Retardation and Perinatal Lethality of Nedd4‐1 Null Mice by Loss of Maternally Inherited Grb10

Abstract

Nedd4‐1, a HECT type ubiquitin ligase, has been proposed to be involved in the regulation of type 1 insulin‐like growth factor receptor (IFG‐1R) from in vitro data. Mice with Nedd4‐1 disrupted were generated in this study. At birth, the body weight of −/− mice was about 1/3 of that of +/+ littermates and they died right after birth. Immature or delayed development was seen throughout, consistent with the notion that the IGF‐1R pathway is inhibited. Mouse embryonic fibroblasts (MEFs) isolated from Nedd4‐1 −/− embryos showed reduced mitogenic activity. IGF‐1R, presented on the plasma membrane of +/+ MEF, was not detected on Nedd4‐1 −/− MEF. Knock‐down of Grb10 using siRNA in the −/− MEF restored IGF‐1R expression. In addition, Nedd4‐1 −/− lethality was rescued by the maternal inheritance of Grb10 disruption (Grb10 −m/+p). Thus, the growth inhibitory effect on IGF‐1R in the absence of Nedd4‐1 is mediated through Grb10.