Overgrowth of a mouse model of the Simpson-Golabi-Behmel syndrome is independent of IGF signaling.

Abstract

The type 1 Simpson-Golabi-Behmel overgrowth syndrome (SGBS1) is caused by loss-of-function mutations of the X-linked GPC3 gene encoding glypican-3, a cell-surface heparan sulfate proteoglycan that apparently plays a negative role in growth control by an unknown mechanism. Mice carrying a Gpc3 gene knockout exhibited several phenotypic features that resemble clinical hallmarks of SGBS1, including somatic overgrowth, renal dysplasia, accessory spleens, polydactyly, and placentomegaly. In Gpc3/DeltaH19 double mutants (lacking GPC3 and also carrying a deletion around the H19 gene region that causes bialellic expression of the closely linked Igf2 gene by imprint relaxation), the Gpc3-null phenotype was exacerbated, while additional SGBS1 features (omphalocele and skeletal defects) were manifested. However, results from a detailed comparative analysis of growth patterns in double mutants lacking GPC3 and also IGF2, IGF1, or the type 1 IGF receptor (IGF1R) provided conclusive genetic evidence inconsistent with the hypothesis that GPC3 acts as a growth suppressor by sequestering or downregulating an IGF ligand. Nevertheless, our data are compatible with a model positing that there is downstream convergence of the independent signaling pathways in which either IGFs or (indirectly) GPC3 participate.

• Authors: Eric Chiao, Peter Fisher, Laura Crisponi, Manila Deiana, Ioannis Dragatsis, David Schlessinger, Giuseppe Pilia, Argiris Efstratiadis
• Journal: Developmental biology (Dev Biol) Vol. 243 Issue 1 Pg. 185-206 (Mar 01 2002) ISSN: 0012-1606 [Print] United States
• PMID: 11846487 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: (C)2002 Elsevier Science (USA).

Chemical References

• Glypicans
• Heparan Sulfate Proteoglycans
• Insulin-Like Growth Factor I
• Insulin-Like Growth Factor II
• Receptor, IGF Type 1

Topics

• Abnormalities, Multiple (genetics)
• Animals
• Disease Models, Animal
• Female
• Gene Deletion
• Gene Expression Regulation
• Glypicans
• Heparan Sulfate Proteoglycans (genetics)
• Insulin-Like Growth Factor I (genetics)
• Insulin-Like Growth Factor II (genetics)
• Male
• Mice
• Mice, Knockout
• Receptor, IGF Type 1 (genetics)
• Signal Transduction (genetics)