BMP signaling orchestrates a transcriptional network to control the fate of mesenchymal stem cells in mice

Development. 2017 Jul 15;144(14):2560-2569. doi: 10.1242/dev.150136. Epub 2017 Jun 2.

Abstract

Signaling pathways are used reiteratively in different developmental processes yet produce distinct cell fates through specific downstream transcription factors. In this study, we used tooth root development as a model with which to investigate how the BMP signaling pathway regulates transcriptional complexes to direct the fate determination of multipotent mesenchymal stem cells (MSCs). We first identified the MSC population supporting mouse molar root growth as Gli1+ cells. Using a Gli1-driven Cre-mediated recombination system, our results provide the first in vivo evidence that BMP signaling activity is required for the odontogenic differentiation of MSCs. Specifically, we identified the transcription factors Pax9, Klf4, Satb2 and Lhx8 as being downstream of BMP signaling and expressed in a spatially restricted pattern that is potentially involved in determining distinct cellular identities within the dental mesenchyme. Finally, we found that overactivation of one key transcription factor, Klf4, which is associated with the odontogenic region, promotes odontogenic differentiation of MSCs. Collectively, our results demonstrate the functional significance of BMP signaling in regulating MSC fate during root development and shed light on how BMP signaling can achieve functional specificity in regulating diverse organ development.

Keywords: BMP; Gli1; Mesenchymal stem cells (MSCs); Odontogenesis.

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Lineage / genetics
  • Cell Lineage / physiology
  • Female
  • Gene Regulatory Networks
  • Kruppel-Like Factor 4
  • Male
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Transgenic
  • Odontoblasts / cytology
  • Odontoblasts / metabolism
  • Odontogenesis / genetics
  • Odontogenesis / physiology
  • Regeneration / genetics
  • Regeneration / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Stem Cell Niche / genetics
  • Stem Cell Niche / physiology
  • Tooth Root / cytology
  • Tooth Root / growth & development
  • Tooth Root / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Zinc Finger Protein GLI1 / genetics
  • Zinc Finger Protein GLI1 / metabolism

Substances

  • Bone Morphogenetic Proteins
  • Gli1 protein, mouse
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Transcription Factors
  • Zinc Finger Protein GLI1