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Dentin Dysplasia in Notum Knockout Mice
P Vogel1, R W Read2, G M Hansen3
1Department of Pathology, Lexicon Pharmaceuticals Inc, The Woodlands, TX, USA peter.vogel@stjude.org.
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.
Insights
NOTUM enzyme deficiency disrupts tooth development, causing defective dentin and enamel fractures. This NOTUM deficiency also impacts kidney development, leading to renal agenesis and reduced survival in mice.
Area of Science:
- Developmental Biology
- Biochemistry
- Genetics
Background:
- Secreted WNT proteins are crucial for cell differentiation and proliferation.
- NOTUM is a secreted enzyme that regulates WNT protein activity by removing an essential palmitoleoylate moiety.
- Understanding NOTUM's role is key to comprehending WNT signaling in development.
Purpose of the Study:
- To investigate the role of NOTUM in mammalian development.
- To characterize the effects of NOTUM deficiency on tooth and kidney morphogenesis.
- To elucidate the impact of altered WNT activity on odontoblast differentiation and function.
Main Methods:
- Production of NOTUM-deficient mice via targeted insertional disruption of the Notum gene.
- Histological and morphological analysis of teeth and kidneys in wild-type and Notum(-/-) mice.
- Assessment of dentin and enamel structure, odontoblast differentiation, and associated pathologies.
Main Results:
- NOTUM deficiency critically impairs dentin morphogenesis, affecting odontoblast differentiation and orientation in incisors and molars.
- Defective dentin in Notum(-/-) mice leads to enamel fracture, increased susceptibility to inflammation, and necrosis.
- NOTUM deficiency is associated with renal agenesis and reduced perinatal viability in mice, indicating a role in kidney development.
Conclusions:
- NOTUM plays a significant role in modulating WNT signaling pathways essential for tooth development, specifically dentin formation.
- NOTUM is also implicated in kidney development, with its deficiency causing renal agenesis.
- These findings highlight the pleiotropic effects of NOTUM in modulating WNT signaling across multiple organ systems.
