Fibroblast growth factor 8 regulates early Meckel's cartilage development via ERK signaling in a stage- and dose-dependent manner

Precise spatiotemporal regulation of epithelial-mesenchymal interactions is fundamental to craniofacial morphogenesis. Fibroblast Growth Factor 8 (FGF8) is a pivotal signaling molecule in early mandibular development; however, its stage-specific regulatory mechanisms remain poorly understood. In this study, we demonstrate that Fgf8 and its receptors exhibit a dynamic, declining expression profile in the mouse mandibular arch between embryonic days 9 (E9) and E11. Using organ and micromass culture systems, we identify a critical developmental window at E10 during which FGF8 exerts a dual effect: it promotes mesenchymal cell expansion while simultaneously suppressing chondrogenic differentiation in a dose-dependent manner. Interestingly, by E11, mandibular cells undergo an autonomous transcriptional shift, reduced proliferative capacity, and show downregulation of proliferation-related gene sets, leading to resistance to FGF8-induced proliferation and chondrogenic inhibition. Mechanistically, we show that FGF8 specifically activates the ERK signaling pathway within the responsive E10 window. Pharmacological inhibition of MEK/ERK signaling successfully rescues the suppressed chondrogenic differentiation, identifying ERK as the key mediator of FGF8-induced chondrogenic inhibition at this stage. Together, our findings reveal that FGF8 acts as a stage-specific regulator that coordinates the transition from cell proliferation to chondrogenic commitment during early Meckel's cartilage development via the ERK pathway.