title: Variant heparan sulfates synthesized in developing mouse brain differentially regulate FGF signaling.
abstract: Heparan sulfates (HSs) exert critical regulatory actions on many proteins, including growth factors, and are essential for normal development. Variations in their specific sulfation patterns are known to regulate binding and signaling of fibroblast growth factors (FGFs) via tyrosine kinase receptors (FGFRs). We previously reported differences in sulfation patterns between HS species expressed by embryonic day 10 (E10) and E12 mouse neural precursor cells. We have examined the abilities of the different HS species to support signaling of the relevant FGF-FGFR combinations expressed early during brain development. For FGF8, which only functions early (E8-E11), E10 HS showed preferential activation. The most potent signaling for FGF8 was via FGFR3c, for which E10 HS was strongly active and E12 HS had no activity. For FGF2, which functions from E10 to E13, HS from both stages showed similar activity and were more potent at activating FGFR1c than the other receptors. Thus, we find a stage-specific correlation with activation. To explore the potential mechanisms for the generation of these stage-specific HS species, we investigated the expression of the HS sulfotransferase (HSST) isozymes responsible for creating diverse sulfation motifs in HS chains. We find that there are stage-specific combinations of HSST isozymes that could underlie the synthesis of different HS species at E10 and E12. Collectively, these data lead us to propose a model in which differential expression of HSSTs results in the synthesis of variant HS species that form functional signaling complexes with FGFs and FGFRs and orchestrate proliferation and differentiation in the developing brain.
authors.affiliation: Department of Anatomy and Cell Biology, University of Melbourne, Victoria, Australia, 3052.
authors.forename: Miriam
authors.initials: M
authors.lastname: Ford-Perriss
authors.forename: Scott E
authors.initials: SE
authors.lastname: Guimond
authors.forename: Una
authors.initials: U
authors.lastname: Greferath
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kita
authors.forename: Kay
authors.initials: K
authors.lastname: Grobe
authors.forename: Hiroko
authors.initials: H
authors.lastname: Habuchi
authors.forename: Koji
authors.initials: K
authors.lastname: Kimata
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.forename: Mark
authors.initials: M
authors.lastname: Murphy
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Turnbull
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001921:Brain / Q000196:embryology* / Q000378:metabolism*; D002478:Cells, Cultured; D004848:Epithelium / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D006497:Heparan Sulfate / Q000096:biosynthesis* / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism
chemical_list: D005346:Fibroblast Growth Factors; D006497:Heparan Sulfate; D007527:Isoenzymes; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D015238:Sulfotransferases; C021350:heparitin sulfotransferase