Overgrowth of a mouse model of the Simpson-Golabi-Behmel syndrome is independent of IGF signaling.
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.
Chiao
Eric
E
Department of Genetics and Development, Columbia University, New York, New York 10032, USA.
Fisher
Peter
P
Crisponi
Laura
L
Deiana
Manila
M
Dragatsis
Ioannis
I
Schlessinger
David
D
Pilia
Giuseppe
G
Efstratiadis
Argiris
A
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1