title: Dentin Dysplasia in Notum Knockout Mice.
abstract: Secreted WNT proteins control cell differentiation and proliferation in many tissues, and NOTUM is a secreted enzyme that modulates WNT morphogens by removing a palmitoleoylate moiety that is essential for their activity. To better understand the role this enzyme in development, the authors produced NOTUM-deficient mice by targeted insertional disruption of the Notum gene. The authors discovered a critical role for NOTUM in dentin morphogenesis suggesting that increased WNT activity can disrupt odontoblast differentiation and orientation in both incisor and molar teeth. Although molars in Notum(-/-) mice had normal-shaped crowns and normal mantle dentin, the defective crown dentin resulted in enamel prone to fracture during mastication and made teeth more susceptible to endodontal inflammation and necrosis. The dentin dysplasia and short roots contributed to tooth hypermobility and to the spread of periodontal inflammation, which often progressed to periapical abscess formation. The additional incidental finding of renal agenesis in some Notum (-/-) mice indicated that NOTUM also has a role in kidney development, with undiagnosed bilateral renal agenesis most likely responsible for the observed decreased perinatal viability of Notum(-/-) mice. The findings support a significant role for NOTUM in modulating WNT signaling pathways that have pleiotropic effects on tooth and kidney development.
authors.affiliation: Department of Pathology, Lexicon Pharmaceuticals Inc, The Woodlands, TX, USA peter.vogel@stjude.org.
authors.forename: P
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Pathology, Lexicon Pharmaceuticals Inc, The Woodlands, TX, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Read
authors.affiliation: Molecular Genetics, Lexicon Pharmaceuticals Inc, The Woodlands, TX, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Hansen
authors.affiliation: Metabolism, Lexicon Pharmaceuticals Inc, The Woodlands, TX, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Powell
authors.affiliation: Lexicon Pharmaceuticals Inc, The Woodlands, TX, USA The Center of Excellence in Medical Genetics Research, Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: P N
authors.initials: PN
authors.lastname: Kantaputra
authors.affiliation: Molecular Genetics, Lexicon Pharmaceuticals Inc, The Woodlands, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Zambrowicz
authors.affiliation: Metabolism, Lexicon Pharmaceuticals Inc, The Woodlands, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Brommage
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003805:Dentin Dysplasia / Q000201:enzymology* / Q000235:genetics; D004950:Esterases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007180:Incisor / Q000254:growth & development; D007668:Kidney / Q000254:growth & development; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008963:Molar / Q000254:growth & development; D016254:Mutagenesis, Insertional; D009805:Odontogenesis / Q000235:genetics; D060449:Wnt Signaling Pathway
chemical_list: D004950:Esterases; C000611122:Notum protein, mouse
keywords: NOTUM; WNT; dentin; dentin dysplasia; dentinogenesis imperfecta; development; kidney agenesis; mouse; odontoblast; tooth