The FGF Family in Humans, Mice, and Zebrafish: Development, Physiology, and Pathophysiology

Abstract

In vertebrates, various signaling pathways are activated in a highly coordinated manner to ensure proper development and morphogenesis. Secreted signaling molecules such as FGFs (Fibroblast growth factors), BMPs (Bone morphogenetic factors), WNTs (Wingless/int), and Hedgehogs play crucial roles in development and morphogenesis by acting over variable distances to influence intracellular signaling events in neighboring cells. FGFs are polypeptide growth factors with diverse biological functions. The human FGF family comprises twenty-two members. The mouse and zebrafish are widely used vertebrate models for studying gene function in vivo. The mouse and zebrafish FGF families comprise twenty-two and twenty-eight members, respectively. These FGFs can be classified as paracrine, endocrine, and intracrine FGFs by their mechanisms of action (Itoh & Ornitz, 2008). Paracrine FGFs (canonical FGFs) mediate biological responses by binding to and activating cell surface tyrosine kinase FGFRs. They act as local paracrine signaling molecules and function in multiple developmental processes including differentiation, cell proliferation, and migration (Itoh & Ornitz, 2008; Beenken & Mohammadi, 2009). Endocrine FGFs are thought to mediate biological responses in an FGFR-dependent manner. However, they function over long distances as endocrine hormones (Kharitonenkov, 2009; Itoh, 2010). In contrast, intracrine FGFs act as FGFR-independent intracellular molecules that regulate the function of voltage-gated sodium channels (Goldfarb et al., 2007; Laezza et al., 2009). Targeted mutagenesis of Fgf genes in mice has elucidated their functions in development and metabolism. Studies with zebrafish Fgf mutant and knockdown embryos also have revealed their functions in development. In addition, evidence for the involvement of FGF signaling in hereditary, paraneoplastic, and metabolic diseases has also accumulated. FGF signaling disorders contribute to pathological conditions. In this article, we provide a succinct review of the FGF family in humans, mice, and zebrafish and their developmental physiological and pathophysiological roles.