Involvement of FGF-8 in initiation, outgrowth and patterning of the vertebrate limb.

Fibroblast Growth Factors (FGFs) are signaling molecules that are important in patterning and growth control during vertebrate limb development. Beads soaked in FGF-1, FGF-2 and FGF-4 are able to induce additional limbs when applied to the flank of young chick embryos (Cohn, M.J., Izpisua-Belmonte, J-C., Abud, H., Heath, J. K., Tickle, C. (1995) Cell 80, 739-746). However, biochemical and expression studies suggest that none of these FGFs is the endogenous signal that initiates limb development. During chick limb development, Fgf-8 transcripts are detected in the intermediate mesoderm and subsequently in the prelimb field ectoderm prior to the formation of the apical ectodermal ridge, structures required for limb initiation and outgrowth, respectively. Later on, Fgf-8 expression is restricted to the ridge cells and expression disappears when the ridge regresses. Application of FGF-8 protein to the flank induces the development of additional limbs. Moreover, we show that FGF-8 can replace the apical ectodermal ridge to maintain Shh expression and outgrowth and patterning of the developing chick limb. Furthermore, continuous and widespread misexpression of FGF-8 causes limb truncations and skeletal alterations with phocomelic or achondroplasia phenotype. Thus, FGF-8 appears to be a key signal involved in initiation, outgrowth and patterning of the developing vertebrate limb.