Yap/Taz function as new mediators of FGF signaling in neural crest-derived cranial suture mesenchymal cells [CUT&Tag]

Cranial suture mesenchymal cells (SMCs), housed by the cranial suture, are required to maintain suture homeostasis and contribute to cranial bone growth, repair, and regeneration. Although their roles in craniofacial development are well-studied, how their functions are orchestrated by intricate signaling networks remain largely unknown. The Fibroblast growth factor (FGF) signaling pathway is a fundamental pathway involved in multiple key cell processes, including stem cell pluripotency and differentiation, and contributes extensively to cranial suture development and homeostasis, yet their precise roles in SMCs are still limited. Neural crest cells (NCCs), a multipotent stem cell population, greatly contribute to craniofacial and suture development, while a big knowledge gap remains regarding the molecular regulation of NCC-derived SMCs. Using NCC-derived SMCs from the frontal sutures of mice as a model, we identified the Hippo signaling downstream effectors, Yap/Taz, as novel mediators of FGF signaling in NCC-derived SMCs. Our data demonstrated that the activation of FGF signaling inhibited osteogenesis in NCC-derived SMC while enhancing their stemness and proliferation by promoting Yap nuclear translocation through pERK1/2, which could be reversed by Yap/Taz deficiency or pERK1/2 inhibition. Additionally, we uncovered a novel interaction between Yap and pERK1/2, and our data suggested that pERK1/2 promote Yap nuclear translocation by phosphorylating Yap at the S128 site to modulate Yap chromatin occupancy on related key Yap targets. Collectively, our data provided the first evidence that FGF signaling regulates the balance between stemness and osteogenesis of NCC-derived SMCs through Yap/Taz. These findings reveal a novel molecular mechanism in NCC-derived SMCs, advancing our understanding of stem cell biology and opening a new avenue for exploring diagnostic and therapeutic methods for craniofacial-related diseases