Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds

被引:392
作者
Ludwig, T
Eggenschwiler, J
Fisher, P
DErcole, AJ
Davenport, ML
Efstratiadis, A
机构
[1] COLUMBIA UNIV COLL PHYS & SURG, DEPT GENET & DEV, NEW YORK, NY 10032 USA
[2] COLUMBIA UNIV COLL PHYS & SURG, DEPT PATHOL, NEW YORK, NY 10032 USA
[3] UNIV N CAROLINA, DEPT PEDIAT, DIV ENDOCRINOL, CHAPEL HILL, NC 27599 USA
关键词
D O I
10.1006/dbio.1996.0182
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
The cation-dependent and cation-independent mannose 6-phosphate receptors (CD- and CI-MPRs) bind the phosphomannosyl recognition marker of lysosomal hydrolases, but in mammals the latter also interacts with insulin-like growth factor II (IGF-II). While IGF signaling is mediated by 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 only from the maternal allele, have increased serum and tissue levels of ICE-II and exhibit overgrowth (135% of normal birthweight) and generalized organomegaly, kinky tail, postaxial polydactyly, heart abnormalities, and edema. These mutants usually die perinatally, but a small minority can survive depending on genetic background and can occasionally reproduce, except for some females characterized by an imperforate vagina and hydrometrocolpos. Consistent with the hypothesis that lethality in the absence of IGF2R-mediated turnover is caused by excess of IGE-II overstimulating IGF1R, Ig/2r mutants are completely rescued when they carry a second mutation eliminating either IGF-II or IGF1R. Normal embryonic development of the Igf1r/Igf2r double mutants, which differ from wild-type siblings only in the pattern of postnatal growth, appears to occur by signaling of IGF-II, being in excess, through a genetically identified unknown receptor, since triple mutants lacking IGF1R, IGF2R, and IGF-II are nonviable dwarfs (30% of normal size). In contrast with the Igf2r/Igf2 double mutants, mice lacking IGF2R/CI-MPR and 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-phosphate-mediated lysosomal enzyme trafficking is essential for viability. (C) 1996 Academic Press, Inc.
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页码:517 / 535
页数:19
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