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Mouse Mutants Lackingthe Type 2 IGFReceptor (IGF2R) AreRescued fromPerinatal LethalityinIgf2andIgf1rNullBackgrounds Thomas LudwigJonathan EggenschwilerPeter Fisher1996 год

Mouse Mutants Lacking the Type 2 IGF Receptor (IGF2R) Are Rescued from Perinatal Lethality inIgf2andIgf1rNull Backgrounds
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Аннотация: 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 imprintedIgf2rgene, which is normally expressed only from the maternal allele, have increased serum and tissue levels of IGF-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 IGF-II overstimulating IGF1R,Igf2rmutants are completely rescued when they carry a second mutation eliminating either IGF-II or IGF1R. Normal embryonic development of theIgf1r/Igf2rdouble 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 theIgf2r/Igf2double 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.
Год издания: 1996
Авторы: Thomas Ludwig, Jonathan Eggenschwiler, Peter Fisher, A. Joseph D’Ercole, Marsha L. Davenport, Argiris Efstratiadis
Издательство: Elsevier BV
Источник: Developmental Biology
Ключевые слова: Genetic Syndromes and Imprinting, Prenatal Screening and Diagnostics, Growth Hormone and Insulin-like Growth Factors
Другие ссылки: Developmental Biology (HTML)
PubMed (HTML)