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

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.