TBX1 protein interactions and microRNA-96-5p regulation controls cell proliferation during craniofacial and dental development: implications for 22q11.2 deletion syndrome

Shan Gao; Myriam Moreno; Steven Eliason; Huojun Cao; Xiao Li; Wenjie Yu; Felicitas B Bidlack; Henry C Margolis; Antonio Baldini; Brad A Amendt

doi:10.1093/hmg/ddu750

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TBX1 protein interactions and microRNA-96-5p regulation controls cell proliferation during craniofacial and dental development: implications for 22q11.2 deletion syndrome

Journal article

Open access

Peer reviewed

TBX1 protein interactions and microRNA-96-5p regulation controls cell proliferation during craniofacial and dental development: implications for 22q11.2 deletion syndrome

Shan Gao, Myriam Moreno, Steven Eliason, Huojun Cao, Xiao Li, Wenjie Yu, Felicitas B Bidlack, Henry C Margolis, Antonio Baldini and Brad A Amendt

Human molecular genetics, Vol.24(8), pp.2330-2348

04/15/2015

DOI: 10.1093/hmg/ddu750

PMCID: PMC4380074

PMID: 25556186

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Abstract

T-box transcription factor TBX1 is the major candidate gene for 22q11.2 deletion syndrome (22q11.2DS, DiGeorge syndrome/Velo-cardio-facial syndrome), whose phenotypes include craniofacial malformations such as dental defects and cleft palate. In this study, Tbx1 was conditionally deleted or over-expressed in the oral and dental epithelium to establish its role in odontogenesis and craniofacial developmental. Tbx1 lineage tracing experiments demonstrated a specific region of Tbx1-positive cells in the labial cervical loop (LaCL, stem cell niche). We found that Tbx1 conditional knockout (Tbx1(cKO)) mice featured microdontia, which coincides with decreased stem cell proliferation in the LaCL of Tbx1(cKO) mice. In contrast, Tbx1 over-expression increased dental epithelial progenitor cells in the LaCL. Furthermore, microRNA-96 (miR-96) repressed Tbx1 expression and Tbx1 repressed miR-96 expression, suggesting that miR-96 and Tbx1 work in a regulatory loop to maintain the correct levels of Tbx1. Cleft palate was observed in both conditional knockout and over-expression mice, consistent with the craniofacial/tooth defects associated with TBX1 deletion and the gene duplication that leads to 22q11.2DS. The biochemical analyses of TBX1 human mutations demonstrate functional differences in their transcriptional regulation of miR-96 and co-regulation of PITX2 activity. TBX1 interacts with PITX2 to negatively regulate PITX2 transcriptional activity and the TBX1 N-terminus is required for its repressive activity. Overall, our results indicate that Tbx1 regulates the proliferation of dental progenitor cells and craniofacial development through miR-96-5p and PITX2. Together, these data suggest a new molecular mechanism controlling pathogenesis of dental anomalies in human 22q11.2DS.

Promoter Regions, Genetic

Facial Bones - metabolism

Cell Proliferation

Humans

Male

MicroRNAs - metabolism

DiGeorge Syndrome - physiopathology

Facial Bones - embryology

T-Box Domain Proteins - genetics

DiGeorge Syndrome - embryology

T-Box Domain Proteins - metabolism

Animals

DiGeorge Syndrome - metabolism

Gene Expression Regulation, Developmental

Tooth - embryology

Protein Binding

Female

Craniofacial Abnormalities

Mice

MicroRNAs - genetics

Tooth - metabolism

DiGeorge Syndrome - genetics

Details

Title: Subtitle: TBX1 protein interactions and microRNA-96-5p regulation controls cell proliferation during craniofacial and dental development: implications for 22q11.2 deletion syndrome
Creators: Shan Gao - Texas A&M University Health Science Center, Houston, TX, USA
Myriam Moreno - Department of Anatomy and Cell Biology, Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA, USA
Steven Eliason - Department of Anatomy and Cell Biology, Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA, USA
Huojun Cao - Texas A&M University Health Science Center, Houston, TX, USA
Xiao Li - Department of Anatomy and Cell Biology, Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA, USA
Wenjie Yu - Department of Anatomy and Cell Biology, Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA, USA
Felicitas B Bidlack - Department of Mineralized Tissue Biology
Henry C Margolis - Center for Biomineralization, Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, USA and
Antonio Baldini - Department of Molecular Medicine and Medical Biotechnology, University Federico II and the Institute of Genetics and Biophysics CNR, Naples, Italy
Brad A Amendt - Department of Anatomy and Cell Biology, Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA, USA, brad-amendt@uiowa.edu
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.24(8), pp.2330-2348
DOI: 10.1093/hmg/ddu750
PMID: 25556186
PMCID: PMC4380074
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: DE 13941 / NIDCR NIH HHS
Language: English
Date published: 04/15/2015
Academic Unit: Orthodontics; Anatomy and Cell Biology; Endodontics; Craniofacial Anomalies Research Center; Dental Research; Internal Medicine
Record Identifier: 9984025375002771

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