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

Research output: Contribution to journalArticle

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 (Tbx1cKO) mice featured microdontia, which coincides with decreased stem cell proliferation in the LaCL of Tbx1cKO mice. In contrast, Tbx1 overexpression 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.

Original languageEnglish
Article numberddu750
Pages (from-to)2330-2348
Number of pages19
JournalHuman Molecular Genetics
Volume24
Issue number8
DOIs
Publication statusPublished - Apr 15 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Fingerprint Dive into the research topics of 'TBX1 protein interactions and microRNA-96-5p regulation controls cell proliferation during craniofacial and dental development: Implications for 22q11.2 deletion syndrome'. Together they form a unique fingerprint.

  • Cite this

    Gao, S., Moreno, M., Eliason, S., Cao, H., Li, X., Yu, W., Bidlack, F. B., Margolis, H. C., Baldini, A., & Amendt, B. A. (2015). 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, 24(8), 2330-2348. [ddu750]. https://doi.org/10.1093/hmg/ddu750