Mouse Twist is required for fibroblast growth factor-mediated epithelial-mesenchymal signalling and cell survival during limb morphogenesis.

Mouse Twist is essential for cranial neural tube, limb and somite development. [Genes Dev. 9 (1995) 686]. To identify the molecular defects disrupting limb morphogenesis, we have analysed expression of mesenchymal transcription factors involved in patterning and the cell-cell signalling cascades controlling limb bud development. These studies establish that Twist is essential for maintenance and progression of limb bud morphogenesis. In particular, the SHH/FGF signalling feedback loop operating between the polarizing region and the apical ectodermal ridge (AER) is disrupted. These defects in epithelial-mesenchymal signalling are most likely a direct consequence of disrupted fibroblast growth factor (FGF) signalling in Twist-deficient limb buds. In early limb buds, down-regulation of Fgf receptor 1 and Fgf10 expression in the mesenchyme occurs concurrent with loss of Fgf4 and Fgf8 expression in the AER. Finally, Twist function, most likely by regulating FGF signalling, is required for cell survival as apoptotic cells are detected in posterior and distal limb bud mesenchyme.