Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease

Abstract

Fibroblast growth factors (FGFs) are a family of structurally related polypeptides that are essential for embryonic development and that function postnatally as homoeostatic factors, in the response to injury, in the regulation of electrical excitability of cells and as hormones that regulate metabolism. In humans, FGF signalling is involved in developmental, neoplastic, metabolic and neurological diseases. Fgfs have been identified in metazoans but not in unicellular organisms. In vertebrates, FGFs can be classified as having intracrine, paracrine and endocrine functions. Paracrine and endocrine FGFs act via cell-surface FGF receptors (FGFRs); while, intracrine FGFs act independent of FGFRs. The evolutionary history of the Fgf family indicates that an intracrine Fgf is the likely ancestor of the Fgf family. During metazoan evolution, the Fgf family expanded in two phases, after the separation of protostomes and deuterostomes and in the evolution of early vertebrates. These expansions enabled FGFs to acquire diverse actions and functions.

Fig. 1

Evolutionary relationships within the human Fgf gene family and schematic representations of FGF structures. (A) Phylogenetic analysis suggests that 22 Fgf genes can be arranged into seven subfamilies containing two to four members each. Branch lengths are proportional to the evolutionary distance between each gene. (B) Gene-location analysis suggests that the Fgf genes can be arranged into seven subfamilies containing three to four members each. FGFs act on target cells in an intracrine, paracrine or endocrine manner. Schematic representations of intracrine, paracrine and endocrine FGF structures are shown. SP, SP* and HB indicate a cleavable secreted signal sequence, an uncleaved bipartite secreted signal sequence and a heparin-binding site, respectively.

Fig. 2

The evolutionary lineage of metazoan organisms and functional evolutionary history of the Fgf gene family. (A) The entire C. elegans, C. intestinalis, mouse and human genomes have been sequenced. The Fgf gene family expanded in two major phases (I and II) during metazoan evolution. Phase I occurred after the separation of protostomes and deutrostomes. Phase II occurred at the early emergence of vertebrates. Mya, million years ago. (B) Fgf13-like is the ancestral gene of the Fgf gene family. Fgf4-like was generated from Fgf13-like by gene duplication during the early stages of metazoan evolution. Fgf5-like, Fgf8-like, Fgf9-like and Fgf10-like were generated from Fgf4-like in phase I by gene duplication. Fgf15/19-like was also generated from Fgf4-like by local gene duplication. Each subfamily further expanded into three or four members via two large-scale genome duplication events in phase II.