title: TGFβ3 regulates periderm removal through ΔNp63 in the developing palate.
abstract: The periderm is a flat layer of epithelium created during embryonic development. During palatogenesis, the periderm forms a protective layer against premature adhesion of the oral epithelia, including the palate. However, the periderm must be removed in order for the medial edge epithelia (MEE) to properly adhere and form a palatal seam. Improper periderm removal results in a cleft palate. Although the timing of transforming growth factor β3 (TGFβ3) expression in the MEE coincides with periderm degeneration, its role in periderm desquamation is not known. Interestingly, murine models of knockout (-/-) TGFβ3, interferon regulatory factor 6 (IRF6) (-/-), and truncated p63 (ΔNp63) (-/-) are born with palatal clefts because of failure of the palatal shelves to adhere, suggesting that these genes regulate palatal epithelial differentiation. However, despite having similar phenotypes in null mouse models, no studies have analyzed the possible association between the TGFβ3 signaling cascade and the IRF6/ΔNp63 genes during palate development. Recent studies indicate that regulation of ΔNp63, which depends on IRF6, facilitates epithelial differentiation. We performed biochemical analysis, gene activity and protein expression assays with palatal sections of TGFβ3 (-/-), ΔNp63 (-/-), and wild-type (WT) embryos, and primary MEE cells from WT palates to analyze the association between TGFβ3 and IRF6/ΔNp63. Our results suggest that periderm degeneration depends on functional TGFβ3 signaling to repress ΔNp63, thereby coordinating periderm desquamation. Cleft palate occurs in TGFβ3 (-/-) because of inadequate periderm removal that impedes palatal seam formation, while cleft palate occurs in ΔNp63 (-/-) palates because of premature fusion.
authors.affiliation: Department of Oral Biology, University of Nebraska Medical Center, Lincoln, Nebraska; Department of Orthodontics, Shandong Provincial Key Laboratory of Oral Biomedicine, School of Stomatology, Shandong University, Jinan, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Hu
authors.forename: Jingpeng
authors.initials: J
authors.lastname: Liu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.forename: Ferhat
authors.initials: F
authors.lastname: Ozturk
authors.forename: Channabasavaiah
authors.initials: C
authors.lastname: Gurumurthy
authors.forename: Rose-Anne
authors.initials: RA
authors.lastname: Romano
authors.forename: Satrajit
authors.initials: S
authors.lastname: Sinha
authors.forename: Ali
authors.initials: A
authors.lastname: Nawshad
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D050835:Interferon Regulatory Factors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010159:Palate / Q000196:embryology / Q000378:metabolism*; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism*; D053782:Transforming Growth Factor beta3 / Q000378:metabolism*
chemical_list: C528250:IRF6 protein, mouse; D050835:Interferon Regulatory Factors; D010750:Phosphoproteins; D015534:Trans-Activators; D053782:Transforming Growth Factor beta3; C486419:Trp63 protein, mouse