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

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.

Sonic Hedgehog Signaling and Tooth Development

“…Just after the beginning of root formation stage of the mouse molar, the HERS secrets Shh [42,43]. Gli1-positive cells are then distributed in the dental mesenchyme around the HERS [44,67,90] and proliferate as the tooth root elongates, differentiating into root-forming cells such as odontoblasts, cementoblasts, and fibroblasts in the dental pulp and the periodontal ligament [44,91]. These Gli1-positive cells have also been shown to have multilineage potential and high colony-forming unit fibroblast (CFU-F) activity in vitro [90].…”

“…Gli1-positive cells are then distributed in the dental mesenchyme around the HERS [44,67,90] and proliferate as the tooth root elongates, differentiating into root-forming cells such as odontoblasts, cementoblasts, and fibroblasts in the dental pulp and the periodontal ligament [44,91]. These Gli1-positive cells have also been shown to have multilineage potential and high colony-forming unit fibroblast (CFU-F) activity in vitro [90]. Furthermore, root elongation is not observed in tooth germ lacking Gli1-positive cells during the root formation stage [44].…”

Dental radiographic findings in 18 individuals with SATB2-associated syndrome

“…Of the 102 enrolled into the SAS clinical registry with complete medical records available at the moment of writing, 37 were clinically evaluated during the 2017 family meeting. Of these, 18 (12 males) were cooperative enough to undergo radiographic characterization at our institution (17) or elsewhere (1) with panoramic and/or periapical radiographs. The median age was 8.5 years (range 2.6-20.5 years).…”

“…SATB2 has been suggested to have a role in several odontogenic processes, including epithelial-mesenchymal interactions during early odontogenesis, odontoblast and ameloblast differentiation, and dentin matrix mineralization [8,17]. In mice, homozygous mutants display abnormalities of the anterior part of the mandible and incisors correlating with the SATB2 expression pattern.…”

BMP‐Smad Signaling Regulates Postnatal Crown Dentinogenesis in Mouse Molar

“…Similarly, odontoblast‐specific disruption of Osx using Col1‐Cre transgenic mice display an increase in cell proliferation and a decrease in Dspp expression, leading to inhibition of odontoblast differentiation and short roots, suggestive of involvement of BMP‐mediated Osx expression in regulating root formation. Moreover, disruption of Bmpr1a in Osx ‐expressing cells results in short roots, whereas mice lacking Bmpr1a in Gli1 ‐expresing cells display no root formation in molars, suggesting the important function of Bmpr1a in the dental mesenchyme for root formation. The Gli1‐Cre marks early odontoblast progenitor cells compared with Osx‐Cre but also marks some dental epithelial populations .…”