title: Activation of Notch1 inhibits medial edge epithelium apoptosis in all-trans retinoic acid-induced cleft palate in mice.
abstract: Administration of all-trans retinoic acid (atRA) on E12.0 (embryonic day 12.0) leads to failure of medial edge epithelium (MEE) disappearance and cleft palate. However, the molecular mechanism underlying the relationship between atRA and MEE remains to be identified. In this study, atRA (200 mg/kg) administered by gavage induced a 75% incidence of cleft palate in C57BL/6 mice. Notch1 was up-regulated in MEE cells in the atRA-treated group compared with the controls at E15.0, together with reduced apoptosis and elevated proliferation. Next, we investigated the mechanisms underlying atRA, Notch1 and MEE degradation in palate organ culture. Our results revealed that down-regulation of Notch1 partially rescued the inhibition of atRA-induced palate fusion. Molecular analysis indicated that atRA increased the expression of Notch1 and Rbpj and decreased the expression of P21. In addition, depletion of Notch1 expression decreased the expression of Rbpj and increased the expression of P21. Moreover, inhibition of Rbpj expression partially reversed atRA-induced MEE persistence and increased P21 expression. These findings demonstrate that atRA inhibits MEE degradation, which in turn induces a cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China.
authors.forename: Shiyi
authors.initials: S
authors.lastname: Dong
authors.affiliation: Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China.
authors.forename: Weicai
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China.
authors.forename: Jianning
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kiang Wu Hospital, Macao, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Stomatology, Nanshan Affiliated Hospital of Guangdong Medical College, Shenzhen, China.
authors.forename: Mu
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China. Electronic address: drhuang52@163.com.
authors.forename: Hongzhang
authors.initials: H
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002972:Cleft Palate / Q000139:chemically induced / Q000473:pathology*; D004848:Epithelium / Q000473:pathology; D005260:Female; D055785:Gene Knockdown Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D013723:Teratogens / Q000633:toxicity*; D014212:Tretinoin / Q000633:toxicity*
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D013723:Teratogens; D014212:Tretinoin
keywords: All-trans retinoic acid; Apoptosis; Medial edge epithelium; Notch1; P21