The roles of FGFs in the early development of vertebrate limbs

‘‘Fibroblast growth factor’’ (FGF) was first identified 25 years ago as a mitogenic activity in pituitary extracts (Armelin 1973; Gospodarowicz 1974). This modest observation subsequently led to the identification of a large family of proteins that affect cell proliferation, differentiation, survival, and motility (for review, see Basilico and Moscatelli 1992; Baird 1994). Recently, evidence has been accumulating that specific members of the FGF family function as key intercellular signaling molecules in embryogenesis (for review, see Goldfarb 1996). Indeed, it may be no exaggeration to say that, in conjunction with the members of a small number of other signaling molecule families including WNT (Parr and McMahon 1994), Hedgehog (HH) (Hammerschmidt et al. 1997), and bone morphogenetic protein (BMP) (Hogan 1996), FGFs are responsible for inducing and/or regulating the subsequent development of most organs in the vertebrate body. The purpose of this review is to discuss the functions performed by members of the FGF family in one of the best-studied vertebrate developmental systems—limb formation. It focuses initially on what is known about FGF function in the established limb bud and then discusses the mechanisms by which the signaling centers that control outgrowth and patterning of the established limb bud are formed, emphasizing possible roles played by FGFs in these processes. Finally, it discusses the potential role of FGFs in the induction of limb development. The insights into the requirement for FGF signaling in bone development that have been gained from analyses of mutations in human and mouse FGF receptor (FGFR) genes will not be discussed, as those studies have been the subject of several recent reviews (Wilkie et al. 1995; Yamaguchi and Rossant 1995; De Moerlooze and Dickson 1997; Webster and Donoghue 1997).