title: Cell surface heparan sulfate chains regulate local reception of FGF signaling in the mouse embryo.
abstract: Heparan sulfate (HS) proteoglycans modulate the activity of multiple growth factors on the cell surface and extracellular matrix. However, it remains unclear how the HS chains control the movement and reception of growth factors into targeted receiving cells during mammalian morphogenetic processes. Here, we found that HS-deficient Ext2 null mutant mouse embryos fail to respond to fibroblast growth factor (FGF) signaling. Marker expression analyses revealed that cell surface-tethered HS chains are crucial for local retention of FGF4 and FGF8 ligands in the extraembryonic ectoderm. Fine chimeric studies with single-cell resolution and expression studies with specific inhibitors for HS movement demonstrated that proteolytic cleavage of HS chains can spread FGF signaling to adjacent cells within a short distance. Together, the results show that spatiotemporal expression of cell surface-tethered HS chains regulate the local reception of FGF-signaling activity during mammalian embryogenesis.
authors.affiliation: Department of Molecular Embryology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka Prefectural Hospital Organization, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Shimokawa
authors.forename: Chiharu
authors.initials: C
authors.lastname: Kimura-Yoshida
authors.forename: Naoko
authors.initials: N
authors.lastname: Nagai
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mukai
authors.forename: Kazumi
authors.initials: K
authors.lastname: Matsubara
authors.forename: Hideto
authors.initials: H
authors.lastname: Watanabe
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Kyoko
authors.initials: K
authors.lastname: Mochida
authors.forename: Isao
authors.initials: I
authors.lastname: Matsuo
mesh_terms: D000818:Animals; D004187:Disaccharides / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006497:Heparan Sulfate / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D009924:Organ Culture Techniques; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D000099065:Exostosin 2
chemical_list: D004187:Disaccharides; D004791:Enzyme Inhibitors; D051519:Fibroblast Growth Factor 4; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D049452:Green Fluorescent Proteins; D006497:Heparan Sulfate; D017351:N-Acetylglucosaminyltransferases; D000099065:Exostosin 2