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

Development. 2016 Nov 15;143(22):4115-4126. doi: 10.1242/dev.138883. Epub 2016 Sep 22.

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.

Keywords: Cleft palate; Lef-1; Periderm; Pitx2; Sox2; Stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Self Renewal / genetics*
  • Cells, Cultured
  • Embryo, Mammalian
  • Epithelium / growth & development
  • Epithelium / metabolism
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks
  • Homeobox Protein PITX2
  • Homeodomain Proteins* / genetics
  • Homeodomain Proteins* / metabolism
  • Incisor / embryology*
  • Incisor / growth & development
  • Incisor / metabolism
  • Lymphoid Enhancer-Binding Factor 1* / genetics
  • Lymphoid Enhancer-Binding Factor 1* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Odontogenesis / genetics*
  • Protein Binding
  • SOXB1 Transcription Factors* / genetics
  • SOXB1 Transcription Factors* / metabolism
  • Stem Cells / physiology*
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism

Substances

  • Homeodomain Proteins
  • Lef1 protein, mouse
  • Lymphoid Enhancer-Binding Factor 1
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Transcription Factors