Piezo2+ mechanosensory neurons orchestrate postnatal development through mechano-chemo-transduction of PDGFA signaling.

Mechanical forces are ubiquitous and essential during vertebrate development, yet how these forces are translated into biochemical signals and regulate development during postnatal organogenesis remains poorly understood. While early embryogenesis relies on cell-autonomous mechanotransduction, the role of sensory innervation-abundant in postnatal stages-has been overlooked. Here, using the postnatal mouse molar development model, a system experiencing sustained mechanical forces and extensive innervation during tooth root formation, we first identify a subpopulation of Piezo2+ mechanosensory neurons in the trigeminal ganglia and reveal these neurons specifically detect tooth root-associated mechanical forces and orchestrate tooth root development via paracrine signaling. Critically, we show that Piezo2 in neurons-not in dental cells-is essential for tooth root morphogenesis, revealing sensory neurons as unexpected master regulators of mesenchymal cell fate. Mechanistically, Piezo2 activation triggers the calcium-dependent secretion of platelet-derived growth factor A, defining the neuronal mechanotransduction pathway that directly converts force into biochemical signals to drive organogenesis. Taken together, our findings demonstrate that Piezo2+ mechanosensory neurons primarily orchestrate mechanical-force-regulated processes during postnatal development. The identification of the PIEZO2-calcium-PDGF axis provides important insight into mechanotransduction by introducing sensory neurons as active architects of tissue development. This work establishes a paradigm in developmental biology, revealing how mechanosensation bridges biomechanics and neurobiology to regulate postnatal organogenesis, with implications for tissue regeneration strategies.