title: Epiprofin/Sp6 regulates Wnt-BMP signaling and the establishment of cellular junctions during the bell stage of tooth development.
abstract: Epiprofin/Specificity Protein 6 (Epfn) is a Krüppel-like family (KLF) transcription factor that is critically involved in tooth morphogenesis and dental cell differentiation. However, its mechanism of action is still not fully understood. We have employed both loss-of-function and gain-of-function approaches to address the role of Epfn in the formation of cell junctions in dental cells and in the regulation of junction-associated signal transduction pathways. We have evaluated the expression of junction proteins in bell-stage incisor and molar tooth sections from Epfn(-/-) mice and in dental pulp MDPC-23 cells overexpressing Epfn. In Epfn(-/-) mice, a dramatic reduction occurs in the expression of tight junction and adherens junction proteins and of the adherens-junction-associated β-catenin protein, a major effector of canonical Wnt signaling. Loss of cell junctions and β-catenin in Epfn(-/-) mice is correlated with a clear decrease in bone morphogenetic protein 4 (BMP-4) expression, a decrease in nestin in the tooth mesenchyme, altered cell proliferation, and failure of ameloblast cell differentiation. Overexpression of Epfn in MDPC-23 cells results in an increased cellular accumulation of β-catenin protein, indicative of upregulation of canonical Wnt signaling. Together, these results suggest that Epfn enhances canonical Wnt/β-catenin signaling in the developing dental pulp mesenchyme, a condition that promotes the activity of other downstream signaling pathways, such as BMP, which are fundamental for cellular induction and ameloblast differentiation. These altered signaling events might underlie some of the most prominent dental defects observed in Epfn(-/-) mice, such as the absence of ameloblasts and enamel, and might throw light on developmental malformations of the tooth, including hyperdontia.
authors.affiliation: Cell Biology & Histology Department, Faculty of Medicine and Dentistry, University of the Basque Country, 48940 Bizkaia, Spain.
authors.forename: Gaskon
authors.initials: G
authors.lastname: Ibarretxe
authors.forename: Maitane
authors.initials: M
authors.lastname: Aurrekoetxea
authors.forename: Olatz
authors.initials: O
authors.lastname: Crende
authors.forename: Iker
authors.initials: I
authors.lastname: Badiola
authors.forename: Lucia
authors.initials: L
authors.lastname: Jimenez-Rojo
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Fernando
authors.initials: F
authors.lastname: Unda
mesh_terms: D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D000565:Ameloblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D003743:Dental Enamel / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D003771:Dental Papilla / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D003782:Dental Pulp / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007180:Incisor / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008963:Molar / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D009024:Morphogenesis / Q000187:drug effects; D009804:Odontoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D014070:Tooth / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D010091:Oximes; D011994:Recombinant Proteins; C498818:Sp6 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3