Neural stem cells shape intracellular calcium landscapes to control cell identity and function

SUMMARY Asymmetrically dividing neural stem cells (NSCs) provide the foundation for brain development by coupling self-renewal to the generation of diverse differentiated progeny. Yet how NSCs actively sculpt intracellular Ca²⁺ dynamics to drive developmental programs and cell behaviors across fate transitions remains poorly understood. Here we identify a role for intracellular Ca 2+ set points in maintaining NSC identity and function in asymmetrically dividing Drosophila neuroblasts (NB). We find that proliferative NBs maintain low baseline cytosolic Ca 2+ , whereas differentiated progeny exhibit elevated cytosolic Ca 2+ . Experimentally increasing cytosolic Ca 2+ slows proliferation and promotes differentiation. We further identify specific Ca 2+ regulatory factors that are required for proliferation. Endoplasmic Reticulum (ER) luminal Ca 2+ also differs by cell fate and depletion of ER Ca 2+ in type II NB by loss of SERCA (Sarcoendoplasmic Reticulum ATPase) is sufficient to reprogram type II NB into a “type I-like” NB fate. Mechanistically, SERCA-dependent ER luminal Ca 2+ is required for Notch receptor processing, trafficking and activation in NBs linking organellar Ca 2+ to a core stem cell signaling pathway. Thus, NSCs and their progeny actively and distinctly shape intracellular Ca 2+ landscapes to drive developmental programs and cell behaviors, with implications for developmental disorders and cancer.