Mitotic spindle assembly: Search-And-Capture model revised

Alex Mogilner is a Professor of Mathematics and Biology at the Courant Institute and
Department of Biology, New York University. Alex received his PhD in applied mathematics
from the University of British Columbia and completed his postdoctoral work in Computational
and Cell Biology at the University of California at Berkeley. His 'dry' lab uses methods of
mathematical and computational modeling and experimental data analysis to understand mechanics
of cell migration, mitosis and galvanotaxis. Alex proposed a model of elastic polymerization
ratchet explaining cell protrusions, models of graded actomyosin contraction and actin
treadmilling array in membrane ‘bag’ predicting motile cell shapes and speeds. Together with
experimentalists, he elucidated feedbacks underlying cell polarization and motility initiation.
He participated in developing and testing a force-balance model of mitotic spindle, and
search-and-capture model of spindle assembly.

Two dominant models of mitotic spindle assembly in are search-and-capture (SAC) and acentrosomal microtubule assembly (AMA). SAC predicts that kinetochores are captured randomly by centrosomal microtubules (MTs), while AMA posits that kinetochore-associated MT bundles get integrated with centrosomal asters at random times. Both models predict a slow spindle assembly plagued by errors. Recent data shows that randomness in kinetochore capture is very low, that spindle assembles in precise stages. We used 3D tracking of centrosomes and kinetochores in mitotic animal cells to inform a computational model, according to which: 1) initially, when the centrosomes are proximal, the centrosomal MTs rapidly and indiscriminately ‘skewer’ the kinetochore MT clouds, effectively establishing lateral MT-kinetochore connections. Then, motor forces lead to rapid centrosomes’ segregation and slight chromosomes’ shifting, so that the chromosomes form a torus-shaped aggregate. When the pole-pole distance reaches a threshold, the polarity sorting of the kinetochore MTs and integration of the kinetochore and centrosomal MTs lead to establishing a vast majority of amphitelic attachments within a narrow time window. The model makes specific predictions about the roles of dynein and CENP-E motors in the spindle assembly, which we test using biochemical and genetic perturbations.

This seminar will be livestreamed and recorded on the Fralin Youtube channel.