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Review
. 2016 Apr 1;30(7):751-71.
doi: 10.1101/gad.277137.115.

Genetic insights into the mechanisms of Fgf signaling

J Richard Brewer  1 , Pierre Mazot  1 , Philippe Soriano  1
Affiliations
Review

Genetic insights into the mechanisms of Fgf signaling

J Richard Brewer et al. Genes Dev. .

Abstract

The fibroblast growth factor (Fgf) family of ligands and receptor tyrosine kinases is required throughout embryonic and postnatal development and also regulates multiple homeostatic functions in the adult. Aberrant Fgf signaling causes many congenital disorders and underlies multiple forms of cancer. Understanding the mechanisms that govern Fgf signaling is therefore important to appreciate many aspects of Fgf biology and disease. Here we review the mechanisms of Fgf signaling by focusing on genetic strategies that enable in vivo analysis. These studies support an important role for Erk1/2 as a mediator of Fgf signaling in many biological processes but have also provided strong evidence for additional signaling pathways in transmitting Fgf signaling in vivo.

Keywords: Erk1/2; Fgfr; fibroblast growth factor; receptor tyrosine kinase; signaling.

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Figures

Figure 1.
Figure 1.
Fgfr alternative splicing facilitates interactions between epithelial and mesenchymal tissues. (A) Alternative splicing of exons 8 and 9 generates b and c isoforms of Fgfr1–3, while exon 10 encodes an invariant transmembrane domain. (B,C) Fgf ligands expressed in epithelium engage Fgfrc isoforms in the adjacent mesenchyme (B), while ligands expressed in the mesenchyme activate Fgfrb isoforms in the epithelium (C). Paracrine signaling also depends on the heparan sulfate proteoglycan (HSPG) coreceptor. (D) Endocrine Fgf ligands use Klotho coreceptors rather than HSPGs. (Ex) exon; (TK) tyrosine kinase. The exon, Fgfr isoform, and cell type specificity are color coded, with blue and green representing epithelium and mesenchyme, respectively.
Figure 2.
Figure 2.
Schematic representation of Fgfr signaling functions. (A) Fgfrs are capable of engaging Erk1/2 through multiple mechanisms, including the Frs2, Shb, and Crk adaptor proteins as well as Plcγ. For simplicity, CrkI, CrkII, and CrkL adaptor proteins are referred to as Crk. Please see the text for further discussion of the role of these signaling proteins. (B) Fgfrs are also capable of engaging several additional signaling pathways, including PI3K/Akt, Pkc, Src, Stat1, p38, and Jnk.
Figure 3.
Figure 3.
Fgf–Erk1/2 signaling regulates the composition of the inner cell mass. The inner cell mass of the blastocyst is composed of epiblast (green) and primitive endoderm (red) cells. Decreasing Fgf or Erk1/2 signaling through pharmacological inhibition or genetically disrupting components of the pathway produces blastocysts with fewer primitive endoderm cells. Conversely, the composition of the inner cell mass can be shifted toward the primitive endoderm cell fate by culturing embryos in an excess of exogenous Fgf ligands.
Figure 4.
Figure 4.
Fgf mediates reciprocal tissue interactions during induction and proximal/distal patterning of the limb. Limb induction depends on mesenchyme-derived Fgf10 engaging Fgfr2b in the adjacent AER (blue). Fgfr2b then functions through Erk1/2 to induce expression of Fgf4, Fgf8, Fgf9, and Fgf17 in the AER, which activate Fgfr1c and Fgfr2c in the adjacent mesenchyme (green). Fgfr1c and Fgfr2c then function to reinforce expression of Fgf10 and instruct limb outgrowth through Erk1/2. (P/D) Proximal/distal.
Figure 5.
Figure 5.
Fgfrs use diverse mechanisms of signaling. Fgfr1 functions through multiple effectors that converge on downstream Erk1/2 signaling in multiple contexts, including axial elongation and development of the pharyngeal arches. In contrast, Fgfr3 uses differential signaling during distinct cellular responses in growth plate chondrocytes. Here, Stat1 is engaged to limit chondrocyte proliferation, and Erk1/2 is subsequently used to inhibit hypertrophic differentiation.
Figure 6.
Figure 6.
Fgf ligands encode distinct biological responses through diverse mechanisms. (A) FGF7 and FGF10 induce distinct lung explant morphologies and cellular responses through differential signal durations. (B) Differential HSPG affinity influences the shape of FGF7 and FGF10 gradients to influence the pattern of proliferating cells and tissue morphology in submandibular gland explants. (C) Fgf7 and Fgf22 instruct differentiation of inhibitory or excitatory presynaptic terminals by engaging distinct Fgfrs in hippocampal CA3 pyramidal neurons.
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