Mitotic Cdc42 waves encode PI(3,4)P₂ signaling and Golgi morphological state to control spindle scaling

Self-organizing waves are observed in numerous biological systems and may encode spatial and temporal information for cellular organization in the absence of prepatterns. In mitotic mast cells, periodic cortical waves emerge before spindle assembly with wave periods that are proportional to cell size. Here, we investigate the mechanisms that govern cortical wave scaling and examine the consequence of wave perturbation on mitotic spindle size scaling. We find that the periods of mitotic waves are regulated by the turnover of phosphatidylinositol 3,4-bisphosphate [PI(3,4)P₂] on the plasma membrane, which depends on inositol polyphosphate-4-phosphatase type II (INPP4B). Genetic depletion of INPP4B increases cortical wave period and spindle length. Intriguingly, we observed mitotic wave periods that tunes continuously during mitosis, indicating the existence of a fast, posttranslational regulatory mechanism for wave scaling. We further find that the regulation of mitotic waves on the plasma membrane is controlled by the sequestering of INPP4B and PI(3,4)P₂ upon mitotic Golgi fragmentation. On the basis of these findings, we propose a cell size-sensing mechanism in which cortical waves act like sonar waves, adjusting their timing and propagation based on the shuttling of signaling proteins between the cell cortex and intracellular organelles. This rapid communication scheme allows the cell to adjust spindle scaling dynamically, ensuring accurate cell division.