Programmed cell death (PCD) in the interdigit region of developing vertebrate limbs generates separated rather than webbed digits. Previous models have proposed that bone morphogenetic proteins (BMPs) directly trigger such PCD; however, they might also act indirectly by regulating fibroblast growth factors (FGFs), which act as cell survival factors. To investigate this question, Mark Lewandoski's group inactivated the BMP receptor gene Bmpr1a specifically in the limb bud's apical ectodermal ridge (AER) -a source of FGF activity. They report on that in mice,BMP signalling mediates AER induction. However, it subsequently inhibits the expression of the AER survival factors Fgf4 and Fgf8,leading to interdigit PCD. By generating conditional mutant mice, the authors show that Bmpr1a inactivation induces Fgf4 and Fgf8upregulation in the AER. Webbing persists in mice where Bmpr1a and Fgf8 are inactivated, but disappears when one copy of Fgf4is also inactivated. Evolutionary alterations in AER FGF activity might account for changes in limb morphology in different species.
