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Mechanisms of FGF gradient formation during embryogenesis - PubMed

Review

Mechanisms of FGF gradient formation during embryogenesis

Revathi Balasubramanian et al. Semin Cell Dev Biol. 2016 May.

Abstract

Fibroblast growth factors (FGFs) have long been attributed to influence morphogenesis in embryonic development. Signaling by FGF morphogen encodes positional identity of tissues by creating a concentration gradient over the developing embryo. Various mechanisms that influence the development of such gradient have been elucidated in the recent past. These mechanisms of FGF gradient formation present either as an extracellular control over FGF ligand diffusion or as a subcellular control of FGF propagation and signaling. In this review, we describe our current understanding of FGF as a morphogen, the extracellular control of FGF gradient formation by heparan sulfate proteoglycans (HSPGs) and mechanisms of intracellular regulation of FGF signaling that influence gradient formation.

Keywords: Fibroblast growth factors; Heparan sulfate proteoglycans; Morphogen.

Copyright © 2015. Published by Elsevier Ltd.

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Figures

Fig. 1
Fig. 1

Biosynthesis and structural diversity of HSPGs: biosynthesis of HSPGs begins in the Golgi apparatus within the cytoplasm. Specific serine residues on the core protein undergo xylosylation that allows for the incorporation of repeating units of GlcA and GlcNAc residues. Ugdh is an enzyme early in the biosynthesis cascade that is required for the synthesis of GlcA and GlcNAc residues. Extl3 is an exostosin-like enzyme that attaches the first GlcNAc to the linkage tetrasaccharide on the core protein. GlcA and GlcNAc residues are added to the side chain by exostoses Ext1 and Ext2. Enzymes Ndst1-4 add N-sulfation groups following the removal of acetyl groups. Additional O-sulfation groups at various positions are added to the chain by enzymes Hs2st, Hs3st1-6, Hs6st1-3. The precursor molecule is then transported to the cell surface or ECM where it undergoes further processing. Heparanase cleaves HS side chains while specific serine proteases cause shedding of HSPGs. Shown here for three kinds of HSPGs: transmembrane type (Syndecans), GPI anchored type (Glypicans) and secreted type (Perlecans, Agrins).

Fig. 2
Fig. 2

Summary of mechanisms regulating FGF gradient formation: FGF ligands from the source cell are bound by HSPG side chains to prevent their diffusion farther away from the source tissue. FGF ligands bound to the receptors initiate FGF signaling cascade that is subject to feedback regulation at various levels, mainly by FGF inhibitors. Alternatively, FGF mRNA can undergo decay as cells move away from the local expression domain. FGF ligands and receptors can also be endocytosed to follow a mostly degradative pathway. FGF ligands can also be locally sequestered by the formation of microluminal structures.

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References

    1. Armelin HA. Pituitary extracts and steroid hormones in the control of 3T3 cell growth. Proc Natl Acad Sci U S A. 1973;70:2702–6. - PMC - PubMed
    1. Wilson R, Leptin M. Fibroblast growth factor receptor-dependent morphogenesis of the Drosophila mesoderm. Philos Trans R Soc Lond Ser B, Biol Sci. 2000;355:891–5. - PMC - PubMed
    1. Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol. 2001;2 REVIEWS 3005. - PMC - PubMed
    1. Borland CZ, Schutzman JL, Stern MJ. Fibroblast growth factor signaling in Caenorhabditis elegans. BioEssays. 2001;23:1120–30. - PubMed
    1. Bottcher RT, Niehrs C. Fibroblast growth factor signaling during early vertebrate development. Endocr Rev. 2005;26:63–77. - PubMed

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