Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith–Wiedemann and Simpson–Golabi–Behmel syndromes

Abstract

In mice, the imprinted Igf2 gene (expressed from the paternal allele), which encodes a growth-promoting factor (IGF-II), is linked closely to the reciprocally imprinted H19 locus on chromosome 7. Also imprinted (expressed from the maternal allele) is the Igf2r gene on chromsome 17 encoding the type 2 IGF receptor that is involved in degradation of excess IGF-II. Double mutant embryos carrying a deletion around the H19 region and also a targeted Igf2r allele, both inherited maternally, have extremely high levels of IGF-II (7-and 11-fold higher than normal in tissues and serum, respectively) as a result of biallelic Igf2 expression (imprint relaxation by deletion of H19-associated sequence) in combination with lack of the IGF2R-mediated IGF-II turnover. This excess of IGF-II causes somatic overgrowth, visceromegaly, placentomegaly, omphalocele, and cardiac and adrenal defects, which are also features of the Beckwith-Wiedemann syndrome (BWS), a genetically complex human disorder associated with chromosomal abnormalities in the 11p15.5 region where the IGF2 gene resides. In addition, the double mutant mouse embryos exhibit skeletal defects and cleft palate, which are manifestations observed frequently in the Simpson-Golabi-Behmel syndrome, another overgrowth disorder overlapping phenotypically, but not genetically, with BWS.

Glypican-3 is involved in cellular protection against mitoxantrone in gastric carcinoma cells

“…It has been proposed that GPC3 negatively regulates insulinlike growth factor-II (IGF-II) activity by competing for IGF-II binding with the signalling receptor for IGF-II, IGF-I receptor . This hypothesis was supported by the generation of IGF-II overexpressing mice that displayed skeletal defects that are typical of SGBS (Eggenschwiler et al, 1997). However, no direct interaction between IGF-II and GPC3 has been detected (Song et al, 1997), indicating that if GPC3 inhibits IGF-II signalling, it does so by a mechanism that is fundamentally different from that of the known receptor.…”

IMP3 is a novel biomarker for adenocarcinoma in situ of the uterine cervix: an immunohistochemical study in comparison with p16INK4a expression

“…IGF-II overexpression has been implicated in the pathogenesis of the tumors in multiple organ systems seen in the Beckwith-Wiedemann syndrome, and the development of breast and liver tumors in transgenic mouse models as well as hepatocellular carcinoma in viral hepatitis mouse models. [16][17][18] Therefore, it is hypothesized that IMP family members are involved in carcinogenesis by stabilizing IGF-II mRNA. However, the IMP proteins also bind and affect other mRNAs and this may also influence the malignant potential of cells.…”

H19 RNA Binds Four Molecules of Insulin-like Growth Factor II mRNA-binding Protein

“…Although the biological significance of the IGF-II peptide is well estab- lished (28,29), the lack of a clue to the biology of H19 RNA has hampered progress considerably. Here, we show that a family of embryonic RNA-binding proteins that were originally identified by the ability to bind to the IGF-II leader 3 mRNA also bind to H19 RNA, thus revealing a common trans-acting factor that may be involved in a mechanistic coupling of the IGF-II and H19 genes at post-transcriptional events such as nuclear export, cytoplasmic localization, and translation.…”