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<p>Hedgehog (HH) signaling is essential in directing the fate determination of postmigratory cranial neural crest cells (CNCCs) to ensure proper craniofacial development. Gli transcription factors (TFs) are established as primary effectors of HH signaling, yet their distinct roles and regulatory mechanisms in governing cell commitment and differentiation of postmigratory CNCCs remain poorly understood. Here, using tooth root as a model, we combined transgenic mouse models with bioinformatic analyses to interrogate the functions of Gli2 and Gli3 in CNCC-derived root progenitor cells of the mouse molar. We revealed that loss of <i>Gli3</i> alone in dental mesenchymal root progenitor cells caused shortened roots and that concurrent loss of <i>Gli2</i> and <i>Gli3</i> exacerbated root malformations, concomitant with profound impairments in cell proliferation and multilineage differentiation, suggesting a synergistic interaction between Gli2 and Gli3 during tooth root development. Mechanistically, Gli2 and Gli3 cooperatively regulated the transcription of <i>Acvr2b</i>, thereby modulating the activity of TGF-β/SMAD signaling within the dental mesenchyme. This Gli2/Gli3-TGF-β signaling cascade was critical for the lineage specification of tooth root progenitor cells during molar morphogenesis. Collectively, this work uncovers synergistic interactions of Gli2 and Gli3 in orchestrating tooth root morphogenesis and provides a novel insight into HH-TGF-β crosstalk in cell fate decisions of postmigratory CNCCs.</p>

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Gli2 and Gli3 synergistically mediate HH-TGF-β crosstalk in mesenchymal progenitor cells to orchestrate tooth root morphogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月12日

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  • Tao Zhou,
  • Linyang Huang,
  • Yaxin Xie,
  • Yijia Yin,
  • Yufei Yao,
  • Li Mei,
  • Paul R. Cooper,
  • Hu Zhao,
  • Xianglong Han,
  • Junjun Jing

摘要

Hedgehog (HH) signaling is essential in directing the fate determination of postmigratory cranial neural crest cells (CNCCs) to ensure proper craniofacial development. Gli transcription factors (TFs) are established as primary effectors of HH signaling, yet their distinct roles and regulatory mechanisms in governing cell commitment and differentiation of postmigratory CNCCs remain poorly understood. Here, using tooth root as a model, we combined transgenic mouse models with bioinformatic analyses to interrogate the functions of Gli2 and Gli3 in CNCC-derived root progenitor cells of the mouse molar. We revealed that loss of Gli3 alone in dental mesenchymal root progenitor cells caused shortened roots and that concurrent loss of Gli2 and Gli3 exacerbated root malformations, concomitant with profound impairments in cell proliferation and multilineage differentiation, suggesting a synergistic interaction between Gli2 and Gli3 during tooth root development. Mechanistically, Gli2 and Gli3 cooperatively regulated the transcription of Acvr2b, thereby modulating the activity of TGF-β/SMAD signaling within the dental mesenchyme. This Gli2/Gli3-TGF-β signaling cascade was critical for the lineage specification of tooth root progenitor cells during molar morphogenesis. Collectively, this work uncovers synergistic interactions of Gli2 and Gli3 in orchestrating tooth root morphogenesis and provides a novel insight into HH-TGF-β crosstalk in cell fate decisions of postmigratory CNCCs.