heparitin-sulfate and Gigantism

Glypicans are a family of cell surface heparan sulfate proteoglycans that play critical roles in multiple cell signaling pathways. Glypicans consist of a globular core, an unstructured stalk modified with sulfated glycosaminoglycan chains, and a glycosylphosphatidylinositol anchor. Though these structural features are conserved, their individual contribution to glypican function remains obscure. Here, we investigate how glypican 3 (GPC3), which is mutated in Simpson-Golabi-Behmel tissue overgrowth syndrome, regulates Hedgehog signaling. We find that GPC3 is necessary for the Hedgehog response, surprisingly controlling a downstream signal transduction step. Purified GPC3 ectodomain rescues signaling when artificially recruited to the surface of GPC3-deficient cells but has dominant-negative activity when unattached. Strikingly, the purified stalk, modified with heparan sulfate but not chondroitin sulfate, is necessary and sufficient for activity. Our results demonstrate a novel function for GPC3-associated heparan sulfate and provide a framework for the functional dissection of glycosaminoglycans by in vivo biochemical complementation. This article has an associated First Person interview with the first author of the paper.

Topics: Abnormalities, Multiple; Arrhythmias, Cardiac; Genetic Diseases, X-Linked; Gigantism; Glypicans; Heart Defects, Congenital; Hedgehog Proteins; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Intellectual Disability; Signal Transduction

Interest in glypican-3 (GPC3), a member of the glypican-related integral membrane heparan sulfate proteoglycans (GRIPS) family, has increased with the finding that it is mutated in the Simpson-Golabi-Behmel overgrowth syndrome (Pilia et al. [1996] Nat. Genet. 12:241-247). The working model suggested that the membrane-bound protein acts locally to limit tissue and organ growth and that it may function by interacting with insulin-like growth factor 2 (IGF2) to limit its local effective level. Here we have tested two predictions of the model. In situ hybridization with the mouse gene cDNA was used to study the expression pattern during embryonic and fetal development. In agreement with predictions, the gene is expressed in precisely the organs that overgrow in its absence; and the patterns of expression of Gpc3 and those reported for Igf2 are strictly correlated.

Topics: Abnormalities, Multiple; Animals; Blotting, Northern; Ectoderm; Gene Expression Regulation, Developmental; Gigantism; Glypicans; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; In Situ Hybridization; Mesoderm; Mice; Phenotype; Proteoglycans; Syndrome

Topics: Abnormalities, Multiple; Animals; Beckwith-Wiedemann Syndrome; Gigantism; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Insulin-Like Growth Factor II; Proteoglycans; Receptor, IGF Type 2; Syndrome