Dynamic remodeling of the transcriptional landscape drives Merkel cell specification and mechanosensory differentiation.

Merkel cells (MCs) are specialized mechanosensory receptor cells essential for touch sensation, exhibiting both epithelial and neuroendocrine characteristics. However, the regulatory processes that shape MC fate remain poorly defined. Using single-cell RNA sequencing, we construct a conserved, triphasic atlas of MC ontogeny comprising an epithelial-like stage, a transitional intermediate phase, and a terminal neuroendocrine state. Importantly, we identify JunB as a priming factor essential for initiating MC differentiation, while Pou4f1 acts as a driver of epithelial-neuroendocrine conversion and subsequent functional integration. Moreover, the gene regulatory network analysis further reveals that TUBB3+ primed cells could differentiate into the MC lineage under the regulation of Barhl1 and Atoh1. Genetic lineage tracing and cross-species analyses validate these mechanisms. Together, our work delineates the transcriptional network orchestrating MC fate determination and mechanosensory differentiation, providing not only mechanistic insights but also highlighting actionable targets relevant to MC carcinoma and sensory restoration.