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1 Departamento de Ciencias Morfológicas y Biología Celular y Animal, Universidad de Extremadura, Badajoz 06071, Spain
2 Instituto Gulbenkian de Ciência, Rue da Quinta Grande, 6 Oeiras, Portugal
3 Department of Anatomy and Physiology, The Wellcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, UK
4 Unidad de Investigación, Hospital Marques de Valdecilla, Santander 39008, Spain
5 Departamento de Anatomía y Biología Celular, Facultad de Medicina, Universidad de Cantabria, Santander 39011, Spain
6 Instituto Cajal, CSIC, Dr Arce 37, Madrid 28002, Spain
*Author for correspondence (e-mail: hurlej{at}unican.es)
Accepted March 29, 2001
We have investigated the role of FGFs in the control of programmed cell death during limb development by analyzing the effects of increasing and blocking FGF signaling in the avian limb bud. BMPs are currently considered as the signals responsible for cell death. Here we show that FGF signaling is also necessary for apoptosis and that the establishment of the areas of cell death is regulated by the convergence of FGF- and BMP-mediated signaling pathways. As previously demonstrated, cell death is inhibited for short intervals (12 hours) after administration of FGFs. However, this initial inhibition is followed (24 hours) by a dramatic increase in cell death, which can be abolished by treatments with a BMP antagonist (Noggin or Gremlin). Conversely, blockage of FGF signaling by applying a specific FGF-inhibitor (SU5402) into the interdigital regions inhibits both physiological cell death and that mediated by exogenous BMPs. Furthermore, FGF receptors 1, 2 and 3 are expressed in the autopodial mesoderm during the regression of the interdigital tissue, and the expression of FGFR3 in the interdigital regions is regulated by FGFs and BMPs in the same fashion as apopotosis. Together our findings indicate that, in the absence of FGF signaling BMPs are not sufficient to trigger apoptosis in the developing limb. Although we provide evidence for a positive influence of FGFs on BMP gene expression, the physiological implication of FGFs in apoptosis appears to result from their requirement 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.
Key words: Apoptosis, BMP, FGF receptors, Snail, MSX2, Syndactyly, Chick, Duck
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