Stem/progenitor cells differentiate into different cell lineages during organ development and morphogenesis. Signaling pathway networks and mechanotransduction are important factors to guide the lineage commitment of stem/progenitor cells during craniofacial tissue morphogenesis. Here, we used tooth root development as a model to explore the roles of FGF signaling and mechanotransduction as well as their interaction in regulating the progenitor cell fate decision. We show that Fgfr1 is expressed in the mesenchymal progenitor cells and their progeny during tooth root development. Loss of Fgfr1 in Gli1⁺ progenitors leads to hyperproliferation and differentiation, which causes narrowed periodontal ligament (PDL) space with abnormal cementum/bone formation leading to ankylosis. We further show that aberrant activation of WNT signaling and mechanosensitive channel Piezo2 occurs after loss of FGF signaling in Gli1-Cre^ER;Fgfr1^fl/fl mice. Overexpression of Piezo2 leads to increased osteoblastic differentiation and decreased Piezo2 leads to downregulation of WNT signaling. Mechanistically, an FGF/PIEZO2/WNT signaling cascade plays a crucial role in modulating the fate of progenitors during root morphogenesis. Downregulation of WNT signaling rescues tooth ankylosis in Fgfr1 mutant mice. Collectively, our findings uncover the mechanism by which FGF signaling regulates the fate decisions of stem/progenitor cells, and the interactions among signaling pathways and mechanotransduction during tooth root development, providing insights for future tooth root regeneration.

干细胞/祖细胞在器官发育和形态发生过程中分化成不同的细胞谱系。信号通路网络和机械转导是颅面组织形态发生过程中指导干细胞/祖细胞谱系定型的重要因素。在这里，我们使用牙根发育作为模型来探索 FGF 信号传导和机械转导的作用以及它们在调节祖细胞命运决定中的相互作用。我们表明 Fgfr1 在牙根发育过程中在间充质祖细胞及其后代中表达。Gli1 ⁺ 祖细胞中 Fgfr1 的缺失导致过度增殖和分化，从而导致牙周韧带 （PDL） 空间变窄，牙骨质/骨骼形成异常，导致强直。我们进一步表明，在 Gli1-Cre^ER 中 FGF 信号丢失后，WNT 信号传导和机械敏感通道 Piezo2 的异常激活发生;Fgfr1^fl/fl 小鼠。Piezo2 的过表达导致成骨细胞分化增加，Piezo2 的减少导致 WNT 信号转导的下调。从机制上讲，FGF/PIEZO2/WNT 信号级联反应在根形态发生过程中调节祖细胞的命运中起着至关重要的作用。WNT 信号转导的下调可挽救 Fgfr1 突变小鼠的牙齿强直。总的来说，我们的研究结果揭示了 FGF 信号调节干细胞/祖细胞命运决定的机制，以及牙根发育过程中信号通路和机械转导之间的相互作用，为未来的牙根再生提供了见解。