LIS1 controls mitosis and mitotic spindle organization via the LIS1-NDEL1-dynein complex

Abstract

Heterozygous LIS1 mutations are responsible for thehuman neuronal migration disorder lissencephaly. Mitotic functions of LIS1 have been suggested from many organisms through out evolution. However, the cellular functions of LIS1 at distinct intracellular compartments suchas the centrosome and the cell cortex have not been well define despecially duringmitotic cell division. Here, we used detailed cellular approaches and time-lapse live cell imaging of mitosis from Lis1 mutant mouse embryonic fibroblasts to reveal critical roles of LIS1 in mitotic spindle regulation. We found that LIS1 is required for the tight control of chromosome congression and segregation to dictate kinetochore-microtubule (MT) interactions and anaphase progression. In addition, LIS1 is essential for the establishment of mitotic spindle pole integrity by maintaining normal centrosome number. Moreover, LIS1 plays crucial roles in mitotic spindle orientation by increasing the density of astral MT plus-end movements toward the cell cortex, which enhances cortical targeting of LIS1-dynein complex. Over expression of NDEL1- dynein and MT stabilization rescues spindle orientation defects in Lis1 mutants, demonstrating that mouse LIS1 acts via the LIS1-NDEL1-dynein complex to regulate astral MT plus-ends dynamics and establish proper contacts of MTs with the cell cortex to ensure precise cell division. © The Author 2013.