Journal article
Tbx1 regulates progenitor cell proliferation in the dental epithelium by modulating Pitx2 activation of p21
Developmental biology, Vol.347(2), pp.289-300
2010
DOI: 10.1016/j.ydbio.2010.08.031
PMCID: PMC3334818
PMID: 20816801
Abstract
Tbx1
−/−
mice present with phenotypic effects observed in DiGeorge syndrome patients however, the molecular mechanisms of
Tbx1 regulating craniofacial and tooth development are unclear. Analyses of the
Tbx1 null mice reveal incisor microdontia, small cervical loops and BrdU labeling reveals a defect in epithelial cell proliferation. Furthermore,
Tbx1 null mice molars are lacking normal cusp morphology. Interestingly, p21 (associated with cell cycle arrest) is up regulated in the dental epithelium of
Tbx1
−/−
embryos. These data suggest that Tbx1 inhibits p21 expression to allow for cell proliferation in the dental epithelial cervical loop, however Tbx1 does not directly regulate p21 expression. A new molecular mechanism has been identified where Tbx1 inhibits Pitx2 transcriptional activity and decreases the expression of Pitx2 target genes, p21, Lef-1 and Pitx2c. p21 protein is increased in PITX2C transgenic mouse embryo fibroblasts (MEF) and chromatin immunoprecipitation assays demonstrate endogenous Pitx2 binding to the p21 promoter. Tbx1 attenuates PITX2 activation of endogenous p21 expression and
Tbx1 null MEFs reveal increased Pitx2a and activation of Pitx2c isoform expression. Tbx1 physically interacts with the PITX2 C-terminus and represses PITX2 transcriptional activation of the p21, LEF-1, and Pitx2c promoters.
Tbx1
−/+
/Pitx2
−/+
double heterozygous mice present with an extra premolar-like tooth revealing a genetic interaction between these factors. The ability of Tbx1 to repress PITX2 activation of
p21 may promote cell proliferation. In addition, PITX2 regulation of
p21 reveals a new role for PITX2 in repressing cell proliferation. These data demonstrate new functional mechanisms for
Tbx1 in tooth morphogenesis and provide a molecular basis for craniofacial defects in DiGeorge syndrome patients.
Details
- Title: Subtitle
- Tbx1 regulates progenitor cell proliferation in the dental epithelium by modulating Pitx2 activation of p21
- Creators
- Huojun Cao - Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USASergio Florez - Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USAMelanie Amen - Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USATuong Huynh - Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USAZiedonis Skobe - Department of Biomineralization, The Forsyth Institute, Boston, MA, USAAntonio Baldini - Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USABrad A Amendt - Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA
- Resource Type
- Journal article
- Publication Details
- Developmental biology, Vol.347(2), pp.289-300
- DOI
- 10.1016/j.ydbio.2010.08.031
- PMID
- 20816801
- PMCID
- PMC3334818
- NLM abbreviation
- Dev Biol
- ISSN
- 0012-1606
- eISSN
- 1095-564X
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000072, name: National Institute of Dental and Craniofacial Research, award: DE 13941, DE 18885
- Language
- English
- Date published
- 2010
- Academic Unit
- Orthodontics; Anatomy and Cell Biology; Endodontics; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984065814502771
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