Colorectal Cancer-Associated Genes Are Associated with Tooth Agenesis and May Have a Role in Tooth Development

Uterine sensitization–associated gene-1 (USAG-1) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor–related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through USAG-1 knockout or anti–USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that USAG-1 controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti–USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

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AXIN2, Tooth Agenesis, and Colorectal Cancer

Epstein's Inborn Errors of Development ◽

10.1093/med/9780199934522.003.0037 ◽

2016 ◽

pp. 331-334

Author(s):

Pekka Nieminen ◽

Laura Lammi ◽

Heikki J. Järvinen

Keyword(s):

Colorectal Cancer ◽

Tooth Agenesis

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The Biology Underlying Abnormalities of Tooth Number in Humans

Journal of Dental Research ◽

10.1177/0022034517720158 ◽

2017 ◽

Vol 96 (11) ◽

pp. 1248-1256 ◽

Cited By ~ 27

Author(s):

E. Juuri ◽

A. Balic

Keyword(s):

Animal Models ◽

Signaling Pathways ◽

Tooth Development ◽

Current Knowledge ◽

Tooth Agenesis ◽

Cellular Mechanisms ◽

Tooth Shape ◽

Tooth Abnormalities ◽

Tooth Number ◽

The Common

In past decades, morphologic, molecular, and cellular mechanisms that govern tooth development have been extensively studied. These studies demonstrated that the same signaling pathways regulate development of the primary and successional teeth. Mutations of these pathways lead to abnormalities in tooth development and number, including aberrant tooth shape, tooth agenesis, and formation of extra teeth. Here, we summarize the current knowledge on the development of the primary and successional teeth in animal models and describe some of the common tooth abnormalities in humans.

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Colorectal cancer and self-reported tooth agenesis

Hereditary Cancer in Clinical Practice ◽

10.1186/1897-4287-12-7 ◽

2014 ◽

Vol 12 (1) ◽

Cited By ~ 7

Author(s):

Noralane M Lindor ◽

Aung Ko Win ◽

Steven Gallinger ◽

Darshana Daftary ◽

Stephen N Thibodeau ◽

...

Keyword(s):

Colorectal Cancer ◽

Tooth Agenesis

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Unbiased association and expression studies identify novel genes for tooth development

10.1101/209684 ◽

2017 ◽

Author(s):

Meredith A. Williams ◽

Claudia Biguetti ◽

Miguel Romero-Bustillos ◽

Kanwal Maheshwari ◽

Nuriye Dinckan ◽

...

Keyword(s):

Colorectal Cancer ◽

Tooth Development ◽

Strong Association ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Independent Dataset ◽

Expression Studies ◽

Genome Wide ◽

Predisposing Genes ◽

Individual Contributions

AbstractPreviously reported co-occurrence of colorectal cancer (CRC) and tooth agenesis (TA) and the overlap in disease-associated gene variants suggest involvement of similar molecular pathways. In this study, we took an unbiased approach and tested genome-wide significant CRC-associated variants for association with isolated TA. Thirty single nucleotide variants (SNVs) in CRC-predisposing genes/loci were genotyped in a discovery dataset composed of 440 individuals with and without isolated TA. Genome-wide significant associations were found between TA and DUSP10 rs6687758 (P=1.25 × 10−9) and ATF1 rs11169552 (P=4.36 × 10−10), with strong association found with CASC8 rs10505477 (P=8.2 × 10−5). Additional CRC marker haplotypes were also significantly associated with TA (P<0.0002). Genotyping an independent dataset consisting of 52 cases with TA and 427 controls confirmed the association with CASC8.Atf1 and Dusp10 expression was detected in the mouse developing teeth from early bud stages to the formation of the complete tooth, suggesting a potential role for these genes and their encoded proteins in tooth development. Our findings suggest Atf1 and Dusp10 as new tooth development genes, while having a role in colorectal cancer. While their individual contributions in tooth development remain to be elucidated, these genes may be considered additional candidates to be tested in future human genetic studies.

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Multivariate GWAS of Structural Dental Anomalies and Dental Caries in a Multi-Ethnic Cohort

Frontiers in Dental Medicine ◽

10.3389/fdmed.2021.771116 ◽

2022 ◽

Vol 2 ◽

Author(s):

Rasha N. Alotaibi ◽

Brian J. Howe ◽

Lina M. Moreno Uribe ◽

Consuelo Valencia Ramirez ◽

Claudia Restrepo ◽

...

Keyword(s):

Dental Caries ◽

Genome Wide Association Study ◽

Tooth Development ◽

Tooth Agenesis ◽

Genetic Associations ◽

Dental Anomalies ◽

Enamel Hypoplasia ◽

Multivariate Tests ◽

Study Approach ◽

Genome Wide

Odontogenesis is a complex process, where disruption can result in dental anomalies and/or increase the risk of developing dental caries. Based on previous studies, certain dental anomalies tend to co-occur in patients, suggesting that these traits may share common genetic and etiological components. The main goal of this study was to implement a multivariate genome wide association study approach to identify genetic variants shared between correlated structural dental anomalies and dental caries. Our cohort (N = 3,579) was derived from the Pittsburgh Orofacial Clefts Study, where multiple dental traits were assessed in both the unaffected relatives of orofacial cleft (OFC) cases (n = 2,187) and unaffected controls (n = 1,392). We identified four multivariate patterns of correlated traits in this data: tooth agenesis, impaction, and rotation (AIR); enamel hypoplasia, displacement, and rotation (HDR); displacement, rotation, and mamelon (DRM); and dental caries, tooth agenesis and enamel hypoplasia (CAH). We analyzed each of these four models using genome-wide multivariate tests of association. No genome-wide statistically significant results were found, but we identified multiple suggestive association signals (P ≤ 10−5) near genes with known biological roles during tooth development, including ADAMTS9 and PRICKLE2 associated with AIR; GLIS3, WDR72, and ROR2 associated with HDR and DRM; ROBO2 associated with DRM; BMP7 associated with HDR; and ROBO1, SMAD2, and MSX2 associated with CAH. This is the first study to investigative genetic associations for multivariate patterns of correlated dental anomalies and dental caries. Further studies are needed to replicate these results in independent cohorts.

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Faculty Opinions recommendation of Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1018319.209416 ◽

2004 ◽

Author(s):

Sue Malcolm

Keyword(s):

Colorectal Cancer ◽

Tooth Agenesis

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Local application of Usag-1 siRNA can promote tooth regeneration in Runx2-deficient mice

Scientific Reports ◽

10.1038/s41598-021-93256-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sayaka Mishima ◽

Katsu Takahashi ◽

Honoka Kiso ◽

Akiko Murashima-Suginami ◽

Yoshihito Tokita ◽

...

Keyword(s):

Tooth Development ◽

Local Application ◽

Mouse Strains ◽

Tooth Agenesis ◽

Renal Capsule ◽

Tooth Formation ◽

Related Transcription Factor ◽

Interfering Rna ◽

Deficient Mice ◽

Mouse Mandibles

AbstractRunt-related transcription factor 2 (Runx2)-deficient mice can be used to model congenital tooth agenesis in humans. Conversely, uterine sensitization-associated gene-1 (Usag-1)-deficient mice exhibit supernumerary tooth formation. Arrested tooth formation can be restored by crossing both knockout-mouse strains; however, it remains unclear whether topical inhibition of Usag-1 expression can enable the recovery of tooth formation in Runx2-deficient mice. Here, we tested whether inhibiting the topical expression of Usag-1 can reverse arrested tooth formation after Runx2 abrogation. The results showed that local application of Usag-1 Stealth small interfering RNA (siRNA) promoted tooth development following Runx2 siRNA-induced agenesis. Additionally, renal capsule transplantation of siRNA-loaded cationized, gelatin-treated mouse mandibles confirmed that cationized gelatin can serve as an effective drug-delivery system. We then performed renal capsule transplantation of wild-type and Runx2-knockout (KO) mouse mandibles, treated with Usag-1 siRNA, revealing that hindered tooth formation was rescued by Usag-1 knockdown. Furthermore, topically applied Usag-1 siRNA partially rescued arrested tooth development in Runx2-KO mice, demonstrating its potential for regenerating teeth in Runx2-deficient mice. Our findings have implications for developing topical treatments for congenital tooth agenesis.

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Stage- and tissue-specific effect of cyclophosphamide during tooth development

European Journal of Orthodontics ◽

10.1093/ejo/cjz002 ◽

2019 ◽

Vol 41 (5) ◽

pp. 519-530

Author(s):

Kohei Nakatsugawa ◽

Hiroshi Kurosaka ◽

Toshihiro Inubushi ◽

Gozo Aoyama ◽

Yukako Isogai ◽

...

Keyword(s):

Root Formation ◽

Histological Analysis ◽

Developmental Stages ◽

Tooth Development ◽

Specific Effect ◽

Tooth Agenesis ◽

Histological Observation ◽

Micro Computed Tomography ◽

Tooth Germs ◽

Morphological Phenotype

Summary Objective The aim of this study was to investigate the toxic effect of cyclophosphamide (CPA) in the development of rodent molars. Methods CPA was administered intraperitoneally in postnatal mice between Day 1 and Day 10, and the morphological phenotype was evaluated at Day 26 using micro-computed tomography and histological analysis, including cell proliferation and cell death analyses. Results M3 molars of the mice who received 100 mg/kg CPA treatment at Day 6 or M2 molars who received treatment at Day 1 resulted in tooth agenesis or marked hypoplasia. Histological observation demonstrated that CPA treatment at Day 6 resulted in shrinkage of the M3 tooth germs, with a significant reduction in the proliferation of apoptotic cells. Conversely, CPA exposure at Day 2, which occurs at around the bud stage of M3, resulted in crown and root hypoplasia, with reduced numbers of cusp and root. In addition, CPA exposure at Day 10, which is the late bell stage of M3, induced root shortening; however, it did not affect crown morphogenesis. Limitations The timing of CPA administration is limited to after birth. Therefore, its effect during the early stages of M1 and M2 could not be investigated. Conclusion Defective phenotypes were evident in both crown and roots due to the effect of CPA. Interestingly, the severity of the phenotypes was associated with the developmental stages of the tooth germs at the time of CPA administration. The cap/early bell stage is the most susceptive timing for tooth agenesis, whereas the late bell stage is predominantly affected in terms of root formation by CPA administration.

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