Essential Role of Heparan Sulfate 2-O-Sulfotransferase in Chick Limb Bud Patterning and Development

Abstract

Although growth factors and morphogens are required for limb bud development and patterning, it is unclear how their signaling and distribution are regulated. Heparan sulfate proteoglycans, which are ubiquitous on the cell surface and in the extracellular matrix including basement membranes, are important regulators of such growth factor signaling and distribution (9 -11). For example, chicken syndecan-3 is expressed throughout the distal mesenchymal cells and plays a role in limb bud outgrowth by controlling FGF signaling between the AER and mesoderm (12). Heparan sulfate proteoglycans play such roles by interacting with these growth factors (13-15); however, it is unclear what role HS chains play in these processes, although HS chains are known to interact with a variety of heparin-binding growth factors (HBGFs) such as FGF.In FGF signaling, the ternary complex composed of HS chains, FGF family molecules, and FGF receptors (FGFRs) is formed on the cell surface (16 -18). Specificities of interactions between heparan sulfate proteoglycan and ligand molecules are thought to reside in the fine structures of HS chains with specific sequences consisting of highly sulfated monosaccharides (N-, 2-O-, and/or 6-O-sulfated) (9,19,20). In fact, the different O-sulfation patterns of HS chains are involved in interactions with FGF family molecules (21-23). These fine structures are generated by the following modification reactions with specific enzymes after the backbone chain of HS is synthesized by the addition of alternating D-glucuronic acid and N-acetyl-D-glucosamine (GlcNAc) residues from the respective UDP sugars by EXT family proteins (24): GlcNAc N-deacetylation and N-sulfation by N-deacetylase/N-sulfotransferase, C-5 epimerization of D-glucuronic acid residues to iduronic acid by C-5 epimerase, and O-sulfations at various places that take place first at C-2 of IdoA and D-glucuronic acid by heparan sulfate 2-O-sulfotransferase (HS2ST), subsequently at C-6 of GlcNAc and N-sulfate-*

Retina development in zebrafish requires the heparan sulfate proteoglycan agrin

“…This hypothesis is noteworthy as the majority of agrin morphant phenotypes are similar to fgf mutant or morphant phenotypes, which include disrupted formation of the MHB, otic vesicle, tail, and eye (Kim et al, 2007). Since Fgfs require heparin binding for activity (Yayon et al, 1991;Kan et al, 1993), Fgf expression and signaling is dependent on heparan sulfate sulfation/structure (Kobayashi et al, 2007), and agrin is a HSPG (Denzer et al, 1995;Tsen et al, 1995), these data are consistent with a mechanism whereby agrin regulation of Fgf signaling contributes to retinal development. Furthermore, previously we have shown that agrin modulates Fgf2-mediated RGC axon outgrowth by a mechanism that includes potentiation of MAP kinase phosphorylation in RGCs (Kim et al, 2003).…”

Preparation of heparan sulfate-like polysaccharide and application in stem cell chondrogenic differentiation

“…Therefore, it can connect extra-and intracellular signaling events, which regulate development, immune response, anticoagulation, stem cell fate, and tissue morphogenesis. 4,22,23 Therefore, sugar chains like heparan sulfate can successfully reproduce a stem cell niche and have therefore applications in regenerative medicine. Their application as biomaterials requires a close structural control and the need for large-scale synthesis.…”

Role of Heparan Sulfate 2-O-Sulfotransferase in Prostate Cancer Cell Proliferation, Invasion, and Growth Factor Signaling

“…They observed renal agenesis as well as eye and skeletal defects. Recently, it was found that 2OST is essential for FGF signaling required in chick limb bud outgrowth and development [39]. …”