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要旨:
Hereditary multiple exostoses (HME) syndrome is an autosomal dominant inherited human disorder, which is characterized by the formation of multiple cartilaginous capped benign tumors (exostoses) that develop from the growth plate of endochondral bones. So far HME has been linked to missense or frameshift mutations in the tumor suppressor genes Ext1 and Ext2. Both are glycosyltransferases involved in heparan sulfate (HS) biosynthesis. It has been shown that in Drosophila the homolog of Ext1, tout velu (ttv), is required for transport of hedgehog (Hh). One of the vertebrate homologs of Hh, Indian hedgehog (Ihh), is a key regulator of endochondral ossification. Ext1 knockout mice are embryonic lethal due to gastrulation defects. We are analyzing a mouse line carrying a hypomorphic allele of Ext1 obtained from a genetrap screen (Ext1-GT). Since Ext1 mutations lead to skeletal deformations in human patients we started to analyze the role of Ext1 and HS-chains during endochondral ossification focussing on the potential role of Ext1 in mediating the Ihh signal. Analysis of the Ext1-GT mutants revealed a severe delay in chondrocyte differentiation. We could show that less amounts of HS in these mutants allow further diffusion of Ihh whereas treatment of limb explants in a limb culture system with heparin leads to a restriction of the Ihh signal. These experiments implicate an important role of HS in establishing a gradient of Ihh signalling in cartilage thereby regulating chondrocyte differentiation.
