Tgf-beta-mediated FasL-Fas-Caspase pathway is crucial during palatogenesis.

Programmed cell death, or apoptosis, is one of the fates of the medial edge epithelium (MEE) during palatal fusion. Transforming growth factor β (Tgf-β) signaling (such as Tgf-β3) is required for the disappearance of the MEE, but the relationship between Tgf-β3 and apoptosis remains unclear. Here we show that the Fas ligand (FasL)-Fas-Caspase extrinsic apoptosis pathway functions during palatal fusion in wild-type mice, but is not detectable in mice lacking Tgf-β3 (Tgf-β3 (-/-) ) or Tgfβr2 in the MEE (K14-Cre;Tgfbr2 (fl/fl)). Inhibition of the FasL-Fas system results in persistence of the midline epithelial seam (MES) and inhibition of caspase activity during palatal organ culture. Moreover, ectopic FasL protein induces apoptosis in MES of K14-Cre;Tgfbr2 (fl/fl) mice. Thus, we conclude that the FasL-Fas-caspase extrinsic apoptosis pathway is regulated by the Tgf-β3 signaling cascade and is essential for palatal fusion during craniofacial development.