FGF-2: Apical Ectodermal Ridge Growth Signal for Chick Limb Development

Abstract

The apical ectodermal ridge permits growth and elongation of amniote limb buds; removal causes rapid changes in mesodermal gene expression, patterned cell death, and truncation of the limb. Ectopic fibroblast growth factor (FGF)-2 supplied to the chick apical bud mesoderm after ridge removal will sustain normal gene expression and cell viability, and allow relatively normal limb development. A bioassay for FGFs demonstrated that FGF-2 was the only detectable FGF in chick limb bud extracts. By distribution and bioactivity, FGF-2 is the prime candidate for the chick limb bud apical ridge growth signal.

The incomplete inactivation of Fgf8 in the limb ectoderm affects the morphogenesis of the anterior autopod through BMP‐mediated cell death

“…In addition, the study of several conditional Fgfr1 ablations using different trans-genic Cre strains (Li et al, 2005;Verheyden et al, 2005) indicates that FGF signaling works in a localized manner with different phenotypes depending on the precise site from which the receptor is removed. All these observations, together with the experiments of AER removal in chick Fallon et al, 1994;Dudley et al, 2002) indicate that FGF signaling is required for the survival of the limb mesoderm, though the mechanism by which reduced FGF signaling results in cell death remains unknown.…”

“…The AER is the thickened ectoderm lining the distal tip of the limb bud thereby separating dorsal from ventral surfaces. The presence of the AER is absolutely required for limb bud outgrowth as it permits survival and/or proliferation and normal gene expression in the subjacent mesoderm Fallon et al, 1994;Dudley et al, 2002). Classical studies showed that the experimental removal of the AER produced truncated limbs whose distal parts failed to develop (Saunders, 1948).…”

“…Several FGFs are capable of substituting for AER function and rescue the truncated limb phenotype if applied immediately after the removal of the AER (Niswander et al, 1993;Fallon et al, 1994). Reciprocally, the drastic reduction in FGF signaling from the AER produced by the simultaneous removal of Fgf8 and Fgf4, the two FGFs with the strongest expression in the AER, results in the failure to form a limb (Sun et al, 2002;Boulet et al, 2004).…”

Re‐programming of expression of the KGFR and bek variants of fibroblast growth factor receptor 2 during limb regeneration in newts (Notophthalmus viridescens)

“…FGF-4 mRNA was observed in the AER but not in the mesenchyme at the time the AER functions to maintain the survival and proliferation of the limb mesenchyme (Niswander and Martin, 1992). Additional experiments in which whole developing limbs minus the AER were cultured in the presence of FGF-4 showed that the limbs grew to levels that exceeded that of limbs with the AER chick limb bud showed that both FGF-2 (Fallon et al, 1994) and FGF-4 (Niswander et al, 1993) could replace the removed AER. Beads soaked in either FGF-2 or FGF-4 were imbedded into stage 18 chick limb buds with the AER removed, and virtually complete outgrowth and patterning of the limbs were achieved with either FGF Fallon et al, 1994).…”

Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning

“…This is supported by several lines of evidence. First, beads soaked in FGF protein can rescue cell death following AER removal, suggesting that FGF can maintain LBM cell survival (Fallon et al, 1994). Second, secreted FGFs exhibit a limited range, possibly as a result of endocytosis and subsequent degradation in lysosomes (Scholpp and Brand, 2004).…”