title: Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development.
abstract: Cleft palate represents one of the most common congenital birth defects in humans. TGFβ signaling, which is mediated by Smad-dependent and Smad-independent pathways, plays a crucial role in regulating craniofacial development and patterning, particularly in palate development. However, it remains largely unknown whether the Smad-independent pathway contributes to TGFβ signaling function during palatogenesis. In this study, we investigated the function of TGFβ activated kinase 1 (Tak1), a key regulator of Smad-independent TGFβ signaling in palate development. We show that Tak1 protein is expressed in both the epithelium and mesenchyme of the developing palatal shelves. Whereas deletion of Tak1 in the palatal epithelium or mesenchyme did not give rise to a cleft palate defect, inactivation of Tak1 in the neural crest lineage using the Wnt1-Cre transgenic allele resulted in failed palate elevation and subsequently the cleft palate formation. The failure in palate elevation in Wnt1-Cre;Tak1(F/F) mice results from a malformed tongue and micrognathia, resembling human Pierre Robin sequence cleft of the secondary palate. We found that the abnormal tongue development is associated with Fgf10 overexpression in the neural crest-derived tongue tissue. The failed palate elevation and cleft palate were recapitulated in an Fgf10-overexpressing mouse model. The repressive effect of the Tak1-mediated noncanonical TGFβ signaling on Fgf10 expression was further confirmed by inhibition of p38, a downstream kinase of Tak1, in the primary cell culture of developing tongue. Tak1 thus functions to regulate tongue development by controlling Fgf10 expression and could represent a candidate gene for mutation in human PRS clefting.
authors: Department of Periodontology, Ninth People's Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
authors: Zhongchen
authors: Z
authors: Song
authors: Chao
authors: C
authors: Liu
authors: Junichi
authors: J
authors: Iwata
authors: Shuping
authors: S
authors: Gu
authors: Akiko
authors: A
authors: Suzuki
authors: Cheng
authors: C
authors: Sun
authors: Wei
authors: W
authors: He
authors: Rong
authors: R
authors: Shu
authors: Lu
authors: L
authors: Li
authors: Yang
authors: Y
authors: Chai
authors: YiPing
authors: Y
authors: Chen
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002972:Cleft Palate / Q000196:embryology* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000378:metabolism* / Q000473:pathology; D051526:Fibroblast Growth Factor 10 / Q000096:biosynthesis / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009432:Neural Crest / Q000196:embryology* / Q000473:pathology; D014059:Tongue / Q000002:abnormalities* / Q000196:embryology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051526:Fibroblast Growth Factor 10; D020930:MAP Kinase Kinase Kinases; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C496463:FGF10 protein, human; C496464:Fgf10 protein, mouse