TGF-beta is required for programmed cell death in interdigital webs of the developing mouse limb

During limb formation massive cell death in the mesenchyme of the interdigital spaces accompanies the formation of free digits. Members of the transforming growth factor beta (TGF-) superfamily were discussed to play a key role in cell-cell interactions, important in the regulation of programmed cell death (PCD). TGF-beta itself is believed to be involved in epithelial-mesenchymal interactions. Here, we demonstrate that PCD is significantly reduced in interdigital spaces of the developing limbs of Tgfbeta2-/-Tgfbeta3-/- double knockouts. The regression of interdigital webs seems to be doses-dependent as interdigital mesenchyme is at least partly reduced in Tgfbeta2-/-Tgfbeta3+/- mutants, whereas interdigital zones of Tgfbeta2-/-Tgfbeta3-/- double knockouts reveal only minimal signs of regression. We conclude that TGF- is a critical extrinsic regulator of PCD.