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

Abstract

TGF-b3, TbR-I, and TGF-b-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-b, big-h3, is coincidentally expressed with TGF-b3 in medial edge epithelial (MEE) cells undergoing apoptosis during normal palatal fusion. big-h3 was also highly expressed in the areas of post-weaning mammary gland cells and developing phalangeal joints in which TGF-b3 or BMP-4-induced apoptosis occurs, respectively. Blocking of big-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 big-h3 expression in the MEE is stimulated by TGF-b3, causes cell death, and consequently results in complete fusion of the apposed palatal shelves.