The LINC complex ensures accurate centrosome positioning during prophase

Abstract

Accurate centrosome separation and positioning during early mitosis relies on force-generating mechanisms regulated by a combination of extracellular, cytoplasmic, and nuclear cues. The identity of the nuclear cues involved in this process remains largely unknown. Here, we investigate how the prophase nucleus contributes to centrosome positioning during the initial stages of mitosis, by using a combination of cell micropatterning, high-resolution live-cell imaging and quantitative 3D cellular reconstruction. We show that in untransformed cells, centrosome positioning is regulated by a nuclear signal, independently of external cues. This nuclear mechanism relies on the linker of nucleoskeleton and cytoskeleton (LINC) complex that controls the loading of dynein on the nuclear envelope (NE), providing spatial cues for robust centrosome positioning on the shortest nuclear axis, prior to nuclear envelope permeabilization (NEP). Moreover, we demonstrate this mechanism is altered in cancer cells, leading to increased chromosome segregation errors. Our results demonstrate how nuclear-cytoskeletal coupling maintains a robust centrosome positioning mechanism to ensure efficient mitotic spindle assembly.