Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality.

Abstract

Murine embryos that inherit a nonfunctional insulin-like growth factor-If/cation-independent mannose 6-phosphate receptor (Igf2r) gene from their fathers are viable and develop normally into adults. However, the majority of mice inheriting the same mutated allele from their mothers die around birth, as a consequence of major cardiac abnormalities. These mice do not express IGF2R in their tissues, are 25-30% larger than their normal siblings, have elevated levels of circulating IGF2 and IGF-binding proteins, and exhibit a slight kink in their tails. These results show that lgf2r is paternally imprinted and reveal that the receptor is crucial for regulating normal fetal growth, circulating levels of IGF2, and heart development.

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.…”

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

“…In knockout model systems the disruption of the igf-Ⅱr gene leads to elevated IGF-Ⅱ levels; but since these animals exhibit lethal organ abnormalities (e.g. organomegaly), no further studies concerning liver tumor development have been carried out [69][70][71] .…”

Demonstration of tumor suppression by mannose 6-phosphate/insulin-like growth factor 2 receptor

“…A number of studies have implicated the Man-6-P/IGF-2 receptor in IGF-2 signaling (Okamoto et al, 1990;Ikezu et al, 1995;McKinnon et al, 2001). However, a signaling role for the receptor has remained controversial and many investigators believe that the receptor's role in IGF-2 function is to moderate IGF-2 action by mediating its endocytosis and degradation (Filson et al, 1993;Lau et al, 1994;Wang et al, 1997). Such a role is consistent with mouse knockout studies, which suggest that the receptor opposes the growthpromoting effects of IGF-2 and with proposals that the receptor acts as a tumor suppressor gene for several cancers (Filson et al, 1993;Lau et al, 1994;Wang et al, 1994Wang et al, , 1997.…”