Skip to main content

Divergent Roles of Heparan Sulfate in Regulation of FGF Signaling During Mammalian Embryogenesis

  • Chapter
  • First Online:
New Principles in Developmental Processes

Abstract

Heparan sulfate proteoglycans, composed of heparan sulfate (HS) glycosaminoglycan chains and core proteins, are distributed at the cell surface as well as in the extracellular matrix (ECM). HS chains play crucial yet divergent roles in regulation of fibroblast growth factor (FGF) signaling extracellularly: as an essential cofactor for ligand–receptor dimerization at the cell surface, positive and negative modulators of stable dimer formation, as a key mediator of active movement of ligands, and as a spatial barrier for passive diffusion in the ECM. These divergent functions are mediated by the local HS structures, for example, chain length and sulfation level, and by the spreading of unanchored HS chains after enzymatic cleavage by proteinases and heparanases. In this way, FGF signaling activity modified by HS participates in multiple cellular processes including cell proliferation, differentiation, survival, and migration during embryonic development. In this chapter, we highlight the essential and cell nonautonomous roles of the cell-surface HS in activation of FGF signaling during mouse extra-embryonic ectoderm development.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Allen BL, Rapraeger AC (2003) Spatial and temporal expression of heparan sulfate in mouse development regulates FGF and FGF receptor assembly. J Cell Biol 163:637–648

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Asada M, Shinomiya M, Suzuki M et al (2009) Glycosaminoglycan affinity of the complete fibroblast growth factor family. Biochim Biophys Acta 1790:40–48

    Article  CAS  PubMed  Google Scholar 

  • Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8:235–253

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bishop JR, Schuksz M, Esko JD (2007) Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature (Lond) 446:1030–1037

    Article  CAS  Google Scholar 

  • BĂĽlow HE, Hobert O (2006) The molecular diversity of glycosaminoglycans shapes animal development. Annu Rev Cell Dev Biol 22:375–407

    Article  PubMed  Google Scholar 

  • Chuang CY, Lord MS, Melrose J et al (2010) Heparan sulfate-dependent signaling of fibroblast growth factor 18 by chondrocyte-derived perlecan. Biochemistry 49:5524–5532

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Corson LB, Yamanaka Y, Lai KM et al (2003) Spatial and temporal patterns of ERK signaling during mouse embryogenesis. Development (Camb) 130:4527–4537

    Article  CAS  Google Scholar 

  • David G, Bai XM, Van der Schueren B et al (1992) Developmental changes in heparan sulfate expression: in situ detection with mAbs. J Cell Biol 119:961–975

    Article  CAS  PubMed  Google Scholar 

  • Dhoot GK, Gustafsson MK, Ai X et al (2001) Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase. Science 293:1663–1666

    Article  CAS  PubMed  Google Scholar 

  • Dorey K, Amaya E (2010) FGF signalling: diverse roles during early vertebrate embryogenesis. Development (Camb) 137:3731–3742

    Article  CAS  Google Scholar 

  • Duchesne L, Octeau V, Bearon RN et al (2012) Transport of fibroblast growth factor 2 in the pericellular matrix is controlled by the spatial distribution of its binding sites in heparan sulfate. PLoS Biol 10:e1001361

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Escobar Galvis ML, Jia J, Zhang X et al (2007) Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate. Nat Chem Biol 3:773–778

    Article  CAS  PubMed  Google Scholar 

  • GarcĂ­a-GarcĂ­a MJ, Anderson KV (2003) Essential role of glycosaminoglycans in Fgf signaling during mouse gastrulation. Cell 114:727–737

    Article  PubMed  Google Scholar 

  • Goetz R, Ohnishi M, Kir S et al (2012) Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. J Biol Chem 287:29134–29146

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Goldfarb M (2012) Voltage-gated sodium channel-associated proteins and alternative mechanisms of inactivation and block. Cell Mol Life Sci 69:1067–1076

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Häcker U, Nybakken K, Perrimon N (2005) Heparan sulphate proteoglycans: the sweet side of development. Nat Rev Mol Cell Biol 6:530–541

    Article  PubMed  Google Scholar 

  • Harada M, Murakami H, Okawa A et al (2009) FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion. Nat Genet 41:289–298

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Higginson JR, Thompson SM, Santos-Silva A et al (2012) Differential sulfation remodelling of heparan sulfate by extracellular 6-O-sulfatases regulates fibroblast growth factor-induced boundary formation by glial cells: implications for glial cell transplantation. J Neurosci 32:15902–15912

    Article  CAS  PubMed  Google Scholar 

  • Hou S, Maccarana M, Min TH et al (2007) The secreted serine protease xHtrA1 stimulates long-range FGF signaling in the early Xenopus embryo. Dev Cell 13:226–241

    Article  CAS  PubMed  Google Scholar 

  • Itoh N, Ornitz DM (2011) Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J Biochem 149:121–130

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jastrebova N, Vanwildemeersch M, Lindahl U et al (2010) Heparan sulfate domain organization and sulfation modulate FGF-induced cell signaling. J Biol Chem 285:26842–26851

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kalinina J, Byron SA, Makarenkova HP et al (2009) Homodimerization controls the fibroblast growth factor 9 subfamily’s receptor binding and heparan sulfate-dependent diffusion in the extracellular matrix. Mol Cell Biol 29:4663–4678

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kim MJ, Cotman SL, Halfter W et al (2003) The heparan sulfate proteoglycan agrin modulates neurite outgrowth mediated by FGF-2. J Neurobiol 55:261–277

    Article  CAS  PubMed  Google Scholar 

  • Kuro-o M (2008) Endocrine FGFs and Klothos: emerging concepts. Trends Endocrinol Metab 19:239–245

    Article  CAS  PubMed  Google Scholar 

  • Lanner F, Rossant J (2010) The role of FGF/Erk signaling in pluripotent cells. Development (Camb) 137:3351–3360

    Article  CAS  Google Scholar 

  • Matsuo I, Kimura-Yoshida C (2013) Extracellular modulation of fibroblast growth factor signaling through heparan sulfate proteoglycans in mammalian development. Curr Opin Genet Dev 23(4):399–407

    Article  CAS  PubMed  Google Scholar 

  • Mohammadi M, Olsen SK, Ibrahimi OA (2005) Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16:107–137

    Article  CAS  PubMed  Google Scholar 

  • Nagamine S, Tamba M, Ishimine H et al (2012) Organ-specific sulfation patterns of heparan sulfate generated by extracellular sulfatases Sulf1 and Sulf2 in mice. J Biol Chem 287:9579–9590

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Otsuki S, Hanson SR, Miyaki S (2010) Extracellular sulfatases support cartilage homeostasis by regulating BMP and FGF signaling pathways. Proc Natl Acad Sci USA 107:10202–10207

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pan Y, Carbe C, Powers A et al (2008) Bud specific N-sulfation of heparan sulfate regulates Shp2-dependent FGF signaling during lacrimal gland induction. Development (Camb) 135:301–310

    Article  CAS  Google Scholar 

  • Patel VN, Knox SM, Likar KM et al (2007) Heparanase cleavage of perlecan heparan sulfate modulates FGF10 activity during ex vivo submandibular gland branching morphogenesis. Development (Camb) 134:4177–4186

    Article  CAS  Google Scholar 

  • Patel VN, Likar KM, Zisman-Rozen S et al (2008) Specific heparan sulfate structures modulate FGF10-mediated submandibular gland epithelial morphogenesis and differentiation. J Biol Chem 283:9308–9317

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pellegrini L, Burke DF, von Delft F et al (2000) Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin. Nature (Lond) 407:1029–1034

    Article  CAS  Google Scholar 

  • Perrimon N, Bernfield M (2000) Specificities of heparan sulphate proteoglycans in developmental processes. Nature (Lond) 404:725–728

    Article  CAS  Google Scholar 

  • Pye DA, Vives RR, Turnbull JE et al (1998) Heparan sulfate oligosaccharides require 6-O-sulfation for promotion of basic fibroblast growth factor mitogenic activity. J Biol Chem 273:22936–22942

    Article  CAS  PubMed  Google Scholar 

  • Qu X, Carbe C, Tao C et al (2011) Lacrimal gland development and Fgf10-Fgfr2b signaling are controlled by 2-O- and 6-O-sulfated heparan sulfate. J Biol Chem 286:14435–14444

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Qu X, Pan Y, Carbe C et al (2012) Glycosaminoglycan-dependent restriction of FGF diffusion is necessary for lacrimal gland development. Development (Camb) 139:2730–2739

    Article  CAS  Google Scholar 

  • Rapraeger AC, Krufka A, Olwin BB (1991) Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation. Science 252:1705–1708

    Article  CAS  PubMed  Google Scholar 

  • Reiland J, Sanderson RD, Waguespack M et al (2004) Heparanase degrades syndecan-1 and perlecan heparan sulfate: functional implications for tumor cell invasion. J Biol Chem 279:8047–8055

    Article  CAS  PubMed  Google Scholar 

  • Schlessinger J, Plotnikov AN, Ibrahimi OA et al (2000) Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol Cell 6:743–750

    Article  CAS  PubMed  Google Scholar 

  • Settembre C, Arteaga-Solis E, McKee MD et al (2008) Proteoglycan desulfation determines the efficiency of chondrocyte autophagy and the extent of FGF signaling during endochondral ossification. Genes Dev 22:2645–2650

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shimokawa K, Kimura-Yoshida C, Nagai N et al (2011) Cell surface heparan sulfate chains regulate local reception of FGF signaling in the mouse embryo. Dev Cell 21:257–272

    Article  CAS  PubMed  Google Scholar 

  • Stickens D, Zak BM, Rougier N et al (2005) Mice deficient in Ext2 lack heparan sulfate and develop exostoses. Development (Camb) 132:5055–5068

    Article  CAS  Google Scholar 

  • Tam PP, Rossant J (2003) Mouse embryonic chimeras: tools for studying mammalian development. Development (Camb) 130:6155–6163

    Article  CAS  Google Scholar 

  • Uchimura K, Lemjabbar-Alaoui H, van Kuppevelt TH et al (2010) Use of a phage display antibody to measure the enzymatic activity of the Sulfs. Methods Enzymol 480:51–64

    Article  CAS  PubMed  Google Scholar 

  • van den Born J, Salmivirta K, Henttinen T et al (2005) Novel heparan sulfate structures revealed by monoclonal antibodies. J Biol Chem 280:20516–20523

    Article  PubMed  Google Scholar 

  • Varki A, Cummings RD, Esko JD et al (eds) (2009) Essentials of glycobiology, 2nd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

    Google Scholar 

  • Wang S, Ai X, Freeman SD et al (2004) QSulf1, a heparan sulfate 6-O-endosulfatase, inhibits fibroblast growth factor signaling in mesoderm induction and angiogenesis. Proc Natl Acad Sci USA 101:4833–4838

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yan D, Lin X (2009) Shaping morphogen gradients by proteoglycans. Cold Spring Harbor Perspect Biol 1:a002493

    Article  Google Scholar 

  • Yayon A, Klagsbrun M, Esko JD et al (1991) Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64:841–848

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Isao Matsuo .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Japan

About this chapter

Cite this chapter

Matsuo, I., Kimura-Yoshida, C., Shimokawa, K. (2014). Divergent Roles of Heparan Sulfate in Regulation of FGF Signaling During Mammalian Embryogenesis. In: Kondoh, H., Kuroiwa, A. (eds) New Principles in Developmental Processes. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54634-4_18

Download citation

Publish with us

Policies and ethics