Journal article
A model for the molecular underpinnings of tooth defects in Axenfeld–Rieger syndrome
Human molecular genetics, Vol.23(1), pp.194-208
01/01/2014
DOI: 10.1093/hmg/ddt411
PMCID: PMC3857954
PMID: 23975681
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.
Details
- Title: Subtitle
- A model for the molecular underpinnings of tooth defects in Axenfeld–Rieger syndrome
- Creators
- Xiao Li - The University of IowaShankar R Venugopalan - The University of IowaHuojun Cao - The University of IowaFlavia O Pinho - The University of IowaMichael L Paine - University of Southern CaliforniaMalcolm L Snead - University of Southern CaliforniaElena V Semina - The Medical College of WisconsinBrad A Amendt - The University of Iowa
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.23(1), pp.194-208
- DOI
- 10.1093/hmg/ddt411
- PMID
- 23975681
- PMCID
- PMC3857954
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Publisher
- Oxford University Press
- Language
- English
- Date published
- 01/01/2014
- Academic Unit
- Orthodontics; Anatomy and Cell Biology; Endodontics; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984025375402771
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