P107. Regulation of interkinetic nuclear migration by cell cycle-coupled active and passive mechanisms in the developing brain

Abstract

Background A hallmark of neurogenesis in the vertebrate brain is the apical-basal nuclear oscillation in polarized neural progenitor cells in the germinal zone. Known as interkinetic nuclear migration (INM), these movements are synchronized with the cell cycle such that nuclei move basally during G1-phase and apically during G2-phase. Such nuclear movements are considered to be critical for progenitor self-renewal. While basal-to-apical nuclear migration is known to involve cytoskeletal motor systems, how migrations in opposite directions are related and linked with the cell cycle are unknown. Results We found that the microtubule-associated protein Tpx2 promotes apical nuclear migration cell-autonomously during G2-phase. Tpx2 becomes detectable in the nucleus during S-phase, and redistributes to the apical process during S to G2 progression to alter microtubule organization. Thus, Tpx2 links cell cycle progression and apical nuclear migration. In contrast, in vivo observations of implanted microbeads, acute S-phase arrest of surrounding cells, and computational modeling suggest that the basal migration of G1-phase nuclei depends on nuclear displacement by G2-phase nuclei migrating apically. Conclusions We conclude that INM proceeds through the intimate linkage of cell-autonomous and non-autonomous mechanisms, in a cell cycle-dependent manner. Autonomous apical nuclear migration is linked with G2-phase through Tpx2, and contributes to the basal migration of G1-phase nuclei non-autonomously. This model of INM not only explains how nuclear migration is associated with the cell cycle, but also describes a robust system enabling the coordination of progenitor cell proliferation with the pseudostratified epithelial architecture of the developing brain.