Role of FGFs in the control of programmed cell death during limb development

We have investigated the role of FGFs in the control of programmed cell dea th during limb development by analyzing the effects of increasing and block ing FGE signaling in the avian limb bud. BMPs are currently considered as t he signals responsible for cell death. Here we show that FGF signaling is a lso necessary for apoptosis and that the establishment of the areas of cell death is regulated by the convergence of FGF- and BMP-mediated signaling p athways. As previously demonstrated, cell death is inhibited for short inte rvals (12 hours) after administration of FGFs, However, this initial inhibi tion is followed (24 hours) by a dramatic increase in cell death, which can be abolished by treatments with a BMP antagonist (Noggin or Gremlin), Conv ersely, blockage of FGF signaling by applying a specific FGF-inhibitor (SU5 402) into the interdigital regions inhibits both physiological cell death a nd that mediated by exogenous BMPs, Furthermore, FGF receptors 1, 2 and 3 a re expressed in the autopodial mesoderm during the regression of the interd igital tissue, and the expression of FGFR3 in the interdigital regions is r egulated by FGFs and BMPs in the same fashion as apopotosis. Together our f indings indicate that, in the absence of FGF signaling BMPs are not suffici ent to trigger apoptosis in the developing limb. Although we provide eviden ce for a positive influence of FGFs on BMP gene expression, the physiologic al implication of FGFs in apoptosis appears to result from their requiremen t for the expression of genes of the apoptotic cascade. We have identified MSX2 and Snail as candidate genes associated with apoptosis the expression of which requires the combined action of FGFs and BMPs.