Overgrowth of a mouse model of Simpson-Golabi-Behmel syndrome is partly mediated by Indian hedgehog.
Loss-of-function mutations of Glypican 3 (Gpc3) cause the Simpson-Golabi-Behmel overgrowth syndrome (SGBS), and developmental overgrowth is observed in Gpc3-null mice, a mouse model for SGBS. We recently reported that GPC3 inhibits Hedgehog (Hh) signalling by inducing its endocytosis and degradation. Here, we show that the developmental overgrowth observed in Gpc3-null mice is, at least in part, a consequence of the hyperactivation of the Hh pathway. We bred Gpc3-null mice with mice that are Hh signalling-deficient owing to the lack of Indian Hh (Ihh), one of the three mammalian Hhs. We found that the Gpc3-null mice showed a 29.9% overgrowth in an Ihh wild-type background, whereas an Ihh-null background partly rescues the overgrowth caused by the lack of Gpc3 as the double mutants were 19.8% bigger than the Ihh-null mice. Consistent with the role of GPC3 in Hh endocytosis and degradation, the Gpc3-null mice show increased levels of Ihh protein and signalling, but similar levels of Ihh messenger RNA.
Capurro
Mariana I
MI
Division of Molecular and Cell Biology, University of Toronto, Toronto, Ontario, Canada.
Li
Fuchuan
F
Filmus
Jorge
J
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D053673:Glypicans / Q000235:genetics / Q000502:physiology; D053823:Hedgehog Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020349:Surface Plasmon Resonance
D053673:Glypicans; D053823:Hedgehog Proteins; C514061:ihh protein, mouse