Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu

Abstract

Heparan sulfate proteoglycans play a vital role in signaling of various growth factors in both Drosophila and vertebrates. In Drosophila, mutations in the tout velu (ttv) gene, a homolog of the mammalian EXT1 tumor suppressor gene, leads to abrogation of glycosaminoglycan (GAG) biosynthesis. This impairs distribution and signaling activities of various morphogens such as Hedgehog (Hh), Wingless (Wg), and Decapentaplegic (Dpp). Mutations in members of the exostosin (EXT) gene family lead to hereditary multiple exostosis in humans leading to bone outgrowths and tumors. In this study, we provide genetic and biochemical evidence that the human EXT1 (hEXT1) gene is conserved through species and can functionally complement the ttv mutation in Drosophila. The hEXT1 gene was able to rescue a ttv null mutant to adulthood and restore GAG biosynthesis.

An Introduction to Proteoglycans and Their Localization

“…Moreover, genetic ablation of EXT1 or EXT2, which encode the components of a heterodimeric protein complex that is the major heparosan polymerase, leads to embryonic lethality. This is true of the mouse, and the equivalent experiments in Drosophila yield the same results, where, remarkably, human EXT1 can rescue flies where the equivalent gene, tout velu, is deleted (Dasgupta et al 2007). Therefore, heparan sulfate is essential for multicellular life.…”

Glycobiology on the fly: Developmental and mechanistic insights from Drosophila

“…Tout velu (ttv) and sister of tout velu (sotv) encode enzymes which form a complex responsible for the sequential, repeating addition of GlcA and GlcNAc to elongate the HS chains (Han et al 2004;Izumikawa et al 2006). Mutations in ttv, sotv, or botv result in impared Wg, Hh and Dpp signaling as well as reduced or abrogated HS synthesis, indicating the crucial role of GAGs in morphogen gradient formation (Toyoda et al 2000;Takei et al 2003;Han et al 2004;Dasgupta et al 2007). Additionally, mutations in the sugarless (sgl) or sulfateless (sfl) genes (encoding the enzymes UDP-glucose dehydrogenase and N-deacetylase/N-sulfotransferase, respectively) ( Figure 1), displayed aberrant tracheal morphogenesis, similar to defects in FGFR signaling (Lin et al 1999;Selleck 2000;Toyoda et al 2000;).…”