Developmental senescence profiling reveals Eda2r as a common mediator in the core senescence program

Cellular senescence is a distinct state of stable cell-cycle arrest coupled to a dynamic secretory phenotype. Although transient senescence contributes to embryonic development and regeneration, its relationship to the chronic forms associated with damage and aging is unclear. Here, we generated a p21-reporter mouse to isolate and transcriptionally profile senescent cells in Apical Ectodermal Ridge of the developing limb. Comparative analysis of these cells with diverse in vitro and in vivo senescence models revealed a conserved gene program encompassing canonical markers and regulators, with previously unassociated factors. Among these, ectodysplasin A2 receptor (Eda2r) emerged as a critical modulator required for senescence-associated transcriptional and functional features. Our findings define a shared molecular framework linking developmental and pathological senescence and identify conserved effectors such as Eda2r as potential targets for therapeutic modulation of senescent cell function.