ArticleHuman molecular genetics2014
A model for the molecular underpinnings of tooth defects in Axenfeld-Rieger syndrome.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 28 citations in OpenAlex.
- PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans.Current biology : CB · 2025Article
- CACNA1S mutation-associated dental anomalies: A calcium channelopathy.Oral diseases · 2024Article
- Epigenetic Regulation of Ameloblast Differentiation by HMGN Proteins.Journal of dental research · 2024Article
- Transcriptional Regulation of Dental Epithelial Cell Fate.International journal of molecular sciences · 2020Review
- Article
- Identification of the Novel Tooth-Specific Transcription Factor AmeloD.Journal of dental research · 2019Article
- FoxO6 regulates Hippo signaling and growth of the craniofacial complex.PLoS genetics · 2018Article
- Review
- Colorectal Cancer-Associated Genes Are Associated with Tooth Agenesis and May Have a Role in Tooth Development.Scientific reports · 2018Article
- A Novel Mutation inMolecular syndromology · 2017Article
- Sox2 and Lef-1 interact with Pitx2 to regulate incisor development and stem cell renewal.Development (Cambridge, England) · 2016Article
- Full Spectrum of Postnatal Tooth Phenotypes in a Novel Irf6 Cleft Lip Model.Journal of dental research · 2016Article
- Waardenburg syndrome type I: Dental phenotypes and genetic analysis of an extended family.Medicina oral, patologia oral y cirugia bucal · 2016Article
- TBX1 protein interactions and microRNA-96-5p regulation controls cell proliferation during craniofacial and dental development: implications for 22q11.2 deletion syndrome.Human molecular genetics · 2015Article
- Identification of the GTPase-activating protein DEP domain containing 1B (DEPDC1B) as a transcriptional target of Pitx2.Experimental cell research · 2015Article
- MSX2 in ameloblast cell fate and activity.Frontiers in physiology · 2014Review
- Axenfeld-Rieger syndrome associated with severe maxillofacial and skeletal anomalies.Journal of oral and maxillofacial pathology : JOMFPArticle
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Patients with Axenfeld-Rieger Syndrome (ARS) present various dental abnormalities, including hypodontia, and enamel hypoplasia. ARS is genetically associated with mutations in the PITX2 gene, which encodes one of the earliest transcription factors to initiate tooth development. Thus, Pitx2 has long been considered as an upstream regulator of the transcriptional hierarchy in early tooth development. However, because Pitx2 is also a major regulator of later stages of tooth development, especially during amelogenesis, it is unclear how mutant forms cause ARS dental anomalies. In this report, we outline the transcriptional mechanism that is defective in ARS. We demonstrate that during normal tooth development Pitx2 activates Amelogenin (Amel) expression, whose product is required for enamel formation, and that this regulation is perturbed by missense PITX2 mutations found in ARS patients. We further show that Pitx2-mediated Amel activation is controlled by chromatin-associated factor Hmgn2, and that Hmgn2 prevents Pitx2 from efficiently binding to and activating the Amel promoter. Consistent with a physiological significance to this interaction, we show that K14-Hmgn2 transgenic mice display a severe loss of Amel expression on the labial side of the lower incisors, as well as enamel hypoplasia-consistent with the human ARS phenotype. Collectively, these findings define transcriptional mechanisms involved in normal tooth development and shed light on the molecular underpinnings of the enamel defect observed in ARS patients who carry PITX2 mutations. Moreover, our findings validate the etiology of the enamel defect in a novel mouse model of ARS.
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