Proteoglycan-mediated effects on Growth-Factor Signalling: D-EXT2
A second area of research is based on our isolation of mutations in the Drosophila homolog of Ext2, a gene that causes Hereditary multiple exostoses (HME), a bone overgrowth syndrome in humans. Biochemical and cell culture studies suggest that human Ext2 and the closely related Ext1 gene encode co-polymerases that synthesize glycosaminoglycans, polysaccharide chains attached to extracellular proteins such as heparan sulfate. Thus it would be predicted that mutations in Ext1 and Ext2 would have similar phenotypes. Surprisingly, our studies indicate that ext2 mutants show defects in multiple growth factor signaling pathways in contrast to the Ext1 ortholog tout velou (ttv) that is known to only affect diffusion of the growth factor Hedgehog (Hh).
Our initial objectives are to characterize the phenotype of mutations in ext2, to establish the role of ext2 in signaling by growth factors of the Wnt, Hh and TGFß family, and to investigate the basis for the differential requirement for ttv and ext2. This work is relevant to birth defects at two levels. In a direct sense, it is pertinent since mutations in the human Ext2 gene cause HME, an inherited autosomal dominant disorder that results from bone overgrowth initiated during childhood. Affected individuals have limbs that may be shorter than normal or develop unevenly in addition to showing characteristic bony projections (exostoses). At another level, the fact that Ext1 and Ext2 are likely to modulate multiple growth factor pathways emphasizes the need to understand their roles in patterning and development during embryogenesis.