Sox2 and Lef-1 interact with Pitx2 to regulate incisor development and stem cell renewal

Zhao Sun, Wenjie Yu, Maria Sanz Navarro, Mason Sweat, Steven Eliason, Thad Sharp, Huan Liu, Kerstin Seidel, Li Zhang, Myriam Moreno, Thomas Lynch, Nathan E. Holton, Laura Rogers, Traci Neff, Michael J. Goodheart, Frederic Michon, Ophir D. Klein, Yang Chai, Adam Dupuy, John F. EngelhardtZhi Chen, Brad A. Amendt

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Sox2 marks dental epithelial stem cells (DESCs) in both mammals and reptiles, and in this article we demonstrate several Sox2 transcriptional mechanisms that regulate dental stem cell fate and incisor growth. Conditional Sox2 deletion in the oral and dental epithelium results in severe craniofacial defects, including impaired dental stem cell proliferation, arrested incisor development and abnormal molar development. The murine incisor develops initially but is absorbed independently of apoptosis owing to a lack of progenitor cell proliferation and differentiation. Tamoxifen-induced inactivation of Sox2 demonstrates the requirement of Sox2 for maintenance of the DESCs in adult mice. Conditional overexpression of Lef-1 in mice increases DESC proliferation and creates a new labial cervical loop stem cell compartment, which produces rapidly growing long tusk-like incisors, and Lef-1 epithelial overexpression partially rescues the tooth arrest in Sox2 conditional knockout mice. Mechanistically, Pitx2 and Sox2 interact physically and regulate Lef-1, Pitx2 and Sox2 expression during development. Thus, we have uncovered a Pitx2-Sox2-Lef-1 transcriptional mechanism that regulates DESC homeostasis and dental development.

Original languageEnglish (US)
Pages (from-to)4115-4126
Number of pages12
JournalDevelopment (Cambridge)
Volume143
Issue number22
DOIs
StatePublished - Nov 15 2016

Keywords

  • Cleft palate
  • Lef-1
  • Periderm
  • Pitx2
  • Sox2
  • Stem cells

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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