Mouse Mutants Lacking the Type 2 IGF Receptor (IGF2R) Are Rescued from Perinatal Lethality inIgf2andIgf1rNull Backgrounds

Abstract

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 Igf2r gene, 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, Igf2r 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.

Role of CTCF Binding Sites in the Igf2/H19 Imprinting Control Region

“…The 17.5-dpc Ϫ(M)/ϩ fetuses and placentae were 122 and 136% of the weight of ϩ/ϩ siblings, respectively ( Table 1). Eleven of 13 fetuses examined exhibited polydactyly of the forepaws, the defect being essentially the same as that described in mutations involving the insulin-like growth factor receptor gene which result in elevated IGFII activity (13,21). As expected from the large size of Ϫ(M)/ϩ fetuses, the concentration of Igf2 mRNA in these fetuses was higher than normal (Fig.…”

The contradictions of the insulin-like growth factor 1 receptor

“…An interesting feature of IGF-IR targeting is that it has only a modest e ect on cells in monolayer cultures. It seems that the IGF-IR is not an absolute requirement for normal growth, as con®rmed also by genetic experiments (Ludwig et al, 1996). It is, however, a strict requirement for anchorage-independent growth .…”

Methylation analysis of 79 patients with growth restriction reveals novel patterns of methylation change at imprinted loci

“…28 Not surprisingly therefore, Igf2r knockout mice are up to 30% larger than wild-type mice. [29][30][31] The expression of human and mouse IGF2R differs: in mice, Igf2r imprinted expression is observed in all fetal and adult tissues; in humans, IGF2R imprinted expression has not been found in adult tissues, but has been found in fetal tissues and Wilms' tumours, in a proportion of samples tested. 32 There is also a difference in the DMRs between these two species: DMR1, in the promoter of the Igf2r gene, occurs only in mice; DMR2 occurs in both species and is located in intron 2, methylated on the maternal allele.…”