Abrogation of heparan sulfate synthesis in<i>Drosophila</i>disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways

Bornemann, Douglas J.; Duncan, Jason; Staatz, William D.; Selleck, Scott B.; Warrior, Rahul

doi:10.1242/dev.01061

Cited by 215 publications

(201 citation statements)

References 66 publications

(71 reference statements)

Supporting

Mentioning

187

Contrasting

Unclassified

Order By: Relevance

“…Our recent studies have demonstrated that both Dally and Dlp are required for Hh and Dpp movement through a restricted diffusion mechanism (Belenkaya et al, 2004;Han et al, 2004b). Regarding Wg morphogen formation, several studies have shown that mutations in genes involved in HS biosynthesis lead to defects in Wg distribution in the wing disc (Baeg et al, 2001;Bornemann et al, 2004;Han et al, 2004a;Luders et al, 2003;Takei et al, 2004). We have previously shown that Dally plays a role in Wg signaling in the wing disc (Lin and Perrimon, 1999).…”

Section: Introductionmentioning

confidence: 99%

Drosophilaglypicans Dally and Dally-like shape the extracellular Wingless morphogen gradient in the wing disc

et al. 2005

View full text Add to dashboard Cite

Drosophila Wingless (Wg) is the founding member of the Wnt family of secreted proteins. During the wing development, Wg acts as a morphogen whose concentration gradient provides positional cues for wing patterning. The molecular mechanism(s) of Wg gradient formation is not fully understood. Here,we systematically analyzed the roles of glypicans Dally and Dally-like protein(Dlp), the Wg receptors Frizzled (Fz) and Fz2, and the Wg co-receptor Arrow(Arr) in Wg gradient formation in the wing disc. We demonstrate that both Dally and Dlp are essential and have different roles in Wg gradient formation. The specificities of Dally and Dlp in Wg gradient formation are at least partially achieved by their distinct expression patterns. To our surprise,although Fz2 was suggested to play an essential role in Wg gradient formation by ectopic expression studies, removal of Fz2 activity does not alter the extracellular Wg gradient. Interestingly, removal of both Fz and Fz2, or Arr causes enhanced extracellular Wg levels, which is mainly resulted from upregulated Dlp levels. We further show that Notum, a negative regulator of Wg signaling, downregulates Wg signaling mainly by modifying Dally. Last, we demonstrate that Wg movement is impeded by cells mutant for both dally and dlp. Together, these new findings suggest that the Wg morphogen gradient in the wing disc is mainly controlled by combined actions of Dally and Dlp. We propose that Wg establishes its concentration gradient by a restricted diffusion mechanism involving Dally and Dlp in the wing disc.

show abstract

Section: Introductionmentioning

confidence: 99%

Drosophilaglypicans Dally and Dally-like shape the extracellular Wingless morphogen gradient in the wing disc

et al. 2005

View full text Add to dashboard Cite

show abstract

“…The Drosophila genome harbors three homologs of the mammalian EXT genes, namely, tout velu (ttv; Bellaiche et al 1998), sister of tout velu (sotv; Bornemann et al 2004;Han et al 2004b), and brother of tout velu (botv; Han et al 2004b). Mutations in either one of the three genes result in impaired HSPG biosynthesis (The et al 1999;Han et al 2004b).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the GPI-linked HSPG Dally has been shown to affect Hh signaling (Desbordes et al 2003;Han et al 2004a). Mutations in any of the three Drosophila EXT genes result in impaired Hh, Wg, and Dpp distribution and signaling (The et al 1999;Bornemann et al 2004;Han et al 2004b;Takei et al 2004).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Furthermore, they bind to and control the biological function of signaling molecules, such as growth factors and morphogens (Allen and Rapraeger, 2003;Johnson et al, 2004;Kreuger et al, 2006). These interactions with signaling molecules underlie in part the importance of HSPGs in development (Lin et al, 1999;Galli et al, 2003;Bornemann et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…The structure of HS defines its interactions with other molecules, and is largely determined by its biosynthesis (Binari et al, 1997;Bellaiche et al, 1998;Bornemann et al, 2004) and posterior enzymatic degradation by heparanase. While disruption of either process appears to disturb normal development, heparanase manipulations have mainly involved exogenous treatment of the developing embryo with bacterial heparatinase (Yost, 1992;Brickman and Gerhart, 1994;Itoh and Sokol, 1994;Walz et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Two promoters with distinct activities in different tissues drive the expression of heparanase in Xenopus

Bertolesi

Michaiel

et al. 2011

Developmental Dynamics

View full text Add to dashboard Cite

In Xenopus laevis embryos, heparanase, the enzyme that degrades heparan sulfate, is synthesized as a preproheparanase (XHpaL) and processed to become enzymatically active (XHpa active). A short nonenzymatic heparanase splice variant (XHpaS) is also expressed. Using immunohistochemistry, Western blot, and heparanase promoter analysis, we studied the dynamic developmental expression of the three heparanases. Our results indicate that (1) all three isoforms are maternally expressed; (2) XHpaS is a developmental variant; (3) in the early embryo, heparanase is localized to both the plasma membrane and the nucleus; (4) several tissues express heparanase, but expression in the developing nervous system is most evident; (5) two promoters with distinct activities in different tissues drive heparanase expression; (6) Oct binding transcription factors may modulate heparanase promoter activity in the early embryo. These data argue that heparanase is expressed widely during development, but localization and levels are finely regulated.

show abstract

Abrogation of heparan sulfate synthesis inDrosophiladisrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways

Cited by 215 publications

References 66 publications

Drosophilaglypicans Dally and Dally-like shape the extracellular Wingless morphogen gradient in the wing disc

Drosophilaglypicans Dally and Dally-like shape the extracellular Wingless morphogen gradient in the wing disc

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

Two promoters with distinct activities in different tissues drive the expression of heparanase in Xenopus

Contact Info

Product

Resources

About