Fibroblast Growth Factors in Development

Abstract

The fibroblast growth factors (FGF) are a family of structurally related proteins that contribute to virtually all aspects of embryonic and postembryonic development, and after birth for regulation of tissue repair and maintenance and control of metabolic physiology in adults. Most FGFs are secreted and act as paracrine or endocrine factors, but a subfamily exists as intracellular proteins. The secreted FGFs bind to their cell surface tyrosine kinase receptors (FGFRs), which when activated trigger intracellular signalling pathways. FGF signalling is evolutionarily conserved in all metazoans and plays a critical role in the development and homeostasis of all multicellular organisms studied so far. A recurring theme of FGFs in development is the reciprocal signalling between different tissues and cell types such as signalling between epithelial and mesenchymal tissues. Abnormal FGF signalling leads to developmental defects, skeletal disorders, metabolic and neuroendocrine disorders and many types of cancer.

Key Concepts

  • FGF signalling is highly conserved in the metazoan evolution.
  • FGF signalling is critical for the normal development of all multicellular organisms.
  • FGFs play a key role in reciprocal signalling between epithelial and mesenchymal tissues.
  • FGF signalling is tightly regulated by the means of differential expression of specific splice isoforms of the receptors, by the requirement of protein co‐factors for the active signalling complex and by post‐translational modification of the receptors.
  • Altered levels of FGF signalling leads to developmental and metabolic defects, impaired regeneration, and different types of cancers.

Keywords: fibroblast growth factor; branching morphogenesis; gastrulation; limb bud; epithelia mesenchyme signalling

Figure 1. FGF receptor domain structure. (a) Schematic representation of mammalian FGFR domain structure. The extracellular domain contains three immunoglobulin‐like domains (D1–D3) and a region of acidic amino acids, the acid box (AB; lavender). The two main alternative splice isoforms IIIb (light blue) and IIIc (green) of FGFR1–3 are shown. SS indicates signal sequence for plasma membrane targeting, and TM indicates transmembrane domain. The intracellular part of FGFR1–4 contains two tyrosine kinase domains (TK). FGF ligands bind to D2–D3 region of the receptors. (b) Schematic representation of the FGFRL1/FGFR5 protein. The extracellular domain has structural similarity of FGFRs, but the short intracellular part lacks tyrosine kinase domain. (c) Schematic representation of the invertebrate FGFR orthologs of C. elegans and D. melanogaster. The C. elegans EGL‐15 shares domain structure with the mammalian FGFRs, except that alternative splicing in the extracellular domain results in two splice isoforms EGL‐15(5A) and EGL‐15(5B) between D1 and D2 (green and blue) rather than in D3. Drosophila Heartless (Htl) and Breathless (Btl) differ in the number of immunoglobulin‐like domains, with Htl having only two, and Btl having five.
Figure 2. FGFR signalling complexes. (a) Paracrine and autocrine FGFs require heparan sulphate proteoglycan (HSPG) co‐factors to bind and activate FGFRs. (b) Endocrine FGFs ‐19, ‐21 and ‐23 require Klotho co‐factors to bind and activate FGFRs. In both (a) and (b), the FGF/FGFR/co‐factor complex formation leads to phosphorylation of the intracellular tyrosine kinase domain (TK) and subsequence recruitment and activation of intracellular adaptor and signalling molecules.
Figure 3. Developmental roles of FGF signalling. (a) FGF signalling in the developing mammalian limb bud demonstrates the tissue‐specific expression of FGFR splice isoforms and the reciprocal signalling between the mesenchyme and the epithelia. The mesenchyme expresses FGF10, which signals to FGFR2IIIb isoform in the ectoderm of the developing limb bud. FGFR2b activation induces expression of FGF8 in the ectoderm, and later as the apical endodermal ridge (AER) thickens, FGF4, ‐9 and ‐17 are also expressed in the AER. The ectodermal FGF4, 8, 9 and 17 signal to FGFR1IIIc and FGFR2IIIc isoforms in the mesenchyme. (b) Tracheal development in Drosophila. All the tracheal cells express Breathless (Btl)/FGFR. However, the cell with the highest Btl activation becomes the leader cell (dark yellow) to initiate a tracheal branch towards Breathless (Btl) ligand (purple). Further branching occurs at sites of patterned expression of Btl.
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Kinnunen, Tarja K(May 2019) Fibroblast Growth Factors in Development. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003306.pub2]