title: Hierarchical interactions of homeodomain and forkhead transcription factors in regulating odontogenic gene expression.
abstract: FoxJ1 is a forkhead transcription factor expressed in multiple tissues during development and a major regulator of cilia development. FoxJ1(-/-) mice present with defects in odontogenesis, and we correlate these defects to hierarchical interactions between homeodomain factors Pitx2 and Dlx2 with FoxJ1 in regulating their expression through direct physical interactions. Chromatin immunoprecipitation assays reveal endogenous Pitx2 and Dlx2 binding to the Dlx2 promoter and Dlx2 binding to the FoxJ1 promoter as well as Dlx2 and FoxJ1 binding to the amelogenin promoter. PITX2 activation of the Dlx2 promoter is attenuated by a direct Dlx2 physical interaction with PITX2. Dlx2 autoregulates its promoter, and Dlx2 transcriptionally activates the downstream gene FoxJ1. Dlx2 and FoxJ1 physically interact and synergistically regulate both Dlx2 and FoxJ1 promoters. Dlx2 and FoxJ1 also activate the amelogenin promoter, and amelogenin is required for enamel formation and late stage tooth development. FoxJ1(-/-) mice maxillary and mandibular incisors are reduced in length and width and have reduced amelogenin expression. FoxJ1(-/-) mice show a reduced and defective ameloblast layer, revealing a biological effect of these transcription factor hierarchies during tooth morphogenesis. These transcriptional mechanisms may contribute to other developmental processes such as neuronal, pituitary, and heart development.
authors.affiliation: Texas A&M University Health Science Center, Institute of Biosciences and Technology, Houston, Texas 77030, USA.
authors.forename: Shankar R
authors.initials: SR
authors.lastname: Venugopalan
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Amen
authors.forename: Sergio
authors.initials: S
authors.lastname: Florez
authors.forename: Diana
authors.initials: D
authors.lastname: Gutierrez
authors.forename: Huojun
authors.initials: H
authors.lastname: Cao
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wang
authors.forename: Brad A
authors.initials: BA
authors.lastname: Amendt
mesh_terms: D053523:Amelogenin / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D047369:Chromatin Immunoprecipitation; D002923:Cilia / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004847:Epithelial Cells / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009805:Odontogenesis / Q000235:genetics*; D025941:Protein Interaction Mapping; D014070:Tooth / Q000196:embryology; D014157:Transcription Factors / Q000378:metabolism; D000097577:Homeobox Protein PITX2
chemical_list: D053523:Amelogenin; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C088334:Distal-less homeobox proteins; C481963:FOXJ1 protein, mouse