glypican-3 controls cellular responses to Bmp4 in limb patterning and skeletal development

Glypicans represent a family of six cell surface heparan sulfate proteoglyc ans in vertebrates. Although no specific in vivo functions have thus far be en described for these proteoglycans, spontaneous mutations in the human an d induced deletions in the mouse glypican-3 (Gpc3) gene result in severe ma lformations and both pre- and postnatal overgrowth, known clinically as the Simpson-Golabi-Behmel syndrome (SGBS). Mice carrying mutant alleles of Gpc 3 created by either targeted gene disruption or gene trapping display a wid e range of phenotypes associated with SOPS including renal cystic dysplasia , ventral wall defects, and skeletal abnormalities that are consistent with the pattern of Gpc3 expression in the mouse embryo. Previous studies in Dr osophila have implicated glypicans in the signaling of decapentaplegic, a B MP homolog. Our experiments with mice show a significant relationship betwe en vertebrate BMP signaling and glypican function; GPC3-deficient animals w ere mated with mice haploinsufficient for bone morphogenetic protein-4 (Bmp 4) and their offspring displayed a high penetrance of postaxial polydactyly and rib malformations not observed in either parent strain. This previousl y unknown link between glypican-3 and BMP4 function provides evidence of a role for glypicans in vertebrate limb patterning and skeletal development a nd suggests a mechanism for the skeletal defects seen in SGBS. (C) 2000 Aca demic Press.