SERCA directs cell migration and branching across species and germ layers.

Branching morphogenesis underlies organogenesis in vertebrates and invertebrates, yet is incompletely understood. Here, we show that the sarco-endoplasmic reticulum Ca reuptake pump (SERCA) directs budding across germ layers and species. Clonal knockdown demonstrated a cell-autonomous role for SERCA in air sac budding. Live imaging of tracheogenesis revealed elevated Ca levels in migratory tip cells as they form branches. SERCA blockade abolished this Ca differential, aborting both cell migration and new branching. Activating protein kinase C (PKC) rescued Ca in tip cells and restored cell migration and branching. Likewise, inhibiting SERCA abolished mammalian epithelial budding, PKC activation rescued budding, while morphogens did not. Mesoderm (zebrafish angiogenesis) and ectoderm ( nervous system) behaved similarly, suggesting a conserved requirement for cell-autonomous Ca signaling, established by SERCA, in iterative budding.