A TGF-β-induced gene, βig-h3, is crucial for the apoptotic disappearance of the medial edge epithelium in palate fusion

TGF-β3, TβR-I, and TGF-β-activated Smad2 has been suggested to be a series of signaling molecules for secondary palate fusion. In this article, we show that a gene induced by TGF-β, βig-h3, is coincidentally expressed with TGF-β3 in medial edge epithelial (MEE) cells undergoing apoptosis during normal palatal fusion. βig-h3 was also highly expressed in the areas of post-weaning mammary gland cells and developing phalangeal joints in which TGF-β3 or BMP-4-induced apoptosis occurs, respectively. Blocking of βig-h3 expression in E12.5 embryos with antisense oligodeoxynucleotides (ODN) resulted in cleft of the secondary palate in 84% of the treated mice that were born. Moreover, the antisense ODN treatment resulted in a failure of apoptosis in the MEE between palatal shelves in physical contact in organ culture. We conclude that βig-h3 expression in the MEE is stimulated by TGF-β3, causes cell death, and consequently results in complete fusion of the apposed palatal shelves.