MOUSE MUTANTS LACKING THE TYPE-2 IGF RECEPTOR (IGF2R) ARE RESCUED FROM PERINATAL LETHALITY IN IGF2 AND IGF1R NULL BACKGROUNDS

The cation-dependent and cation-independent mannose 6-phosphate recept ors (CD- and CI-MPRs) bind the phosphomannosyl recognition marker of l ysosomal hydrolases, but in mammals the latter also interacts with ins ulin-like growth factor II (IGF-II). While IGF signaling is mediated b y the type 1 IGF receptor (IGF1R), the type 2 receptor (IGF2R/CI-MPR) serves IGF-II turnover. Mouse mutants inheriting maternally a targeted disruption of the imprinted Ig/2r gene, which is normally expressed o nly from the maternal allele, have increased serum and tissue levels o f ICE-II and exhibit overgrowth (135% of normal birthweight) and gener alized organomegaly, kinky tail, postaxial polydactyly, heart abnormal ities, and edema. These mutants usually die perinatally, but a small m inority can survive depending on genetic background and can occasional ly reproduce, except for some females characterized by an imperforate vagina and hydrometrocolpos. Consistent with the hypothesis that letha lity in the absence of IGF2R-mediated turnover is caused by excess of IGE-II overstimulating IGF1R, Ig/2r mutants are completely rescued whe n they carry a second mutation eliminating either IGF-II or IGF1R. Nor mal embryonic development of the Igf1r/Igf2r double mutants, which dif fer from wild-type siblings only in the pattern of postnatal growth, a ppears to occur by signaling of IGF-II, being in excess, through a gen etically identified unknown receptor, since triple mutants lacking IGF 1R, IGF2R, and IGF-II are nonviable dwarfs (30% of normal size). In co ntrast with the Igf2r/Igf2 double mutants, mice lacking IGF2R/CI-MPR a nd CD-MPR survive in an IGF-II null background at a very low frequency and only for a few postnatal weeks, indicating that the mannose 6-pho sphate-mediated lysosomal enzyme trafficking is essential for viabilit y. (C) 1996 Academic Press, Inc.