A computational model of the early stages of acentriolar meiotic spindle assembly
2019
Authors: Letort G, Bennabi I, Dmitrieff S, Nedelec F, Verlhac MH, Terret ME
CellNetworks People: Nédélec François
Journal: Mol Biol Cell. 2019 Jan 16:mbcE18100644. doi: 10.1091/mbc.E18-10-0644

The mitotic spindle is an ensemble of microtubules responsible for the repartition of the chromosomal content between the two daughter cells during division. In metazoans, spindle assembly is a gradual process involving dynamic microtubules and recruitment of numerous associated proteins and motors. During mitosis, centrosomes organize and nucleate the majority of spindle microtubules. In contrast, oocytes lack canonical centrosomes but are still able to form bipolar spindles, starting from an initial ball which self-organizes in several hours. Interfering with early steps of meiotic spindle assembly can lead to erroneous chromosome segregation. Although not fully elucidated, this process is known to rely on antagonistic activities of plus-end and minus-end directed motors. We developed a model of early meiotic spindle assembly in mouse oocytes, including key factors such as microtubule dynamics and chromosome movement. We explored how the balance between plus-end and minus-end directed motors, as well as the influence of microtubule nucleation, impacts spindle morphology. In a refined model, we added spatial regulation of microtubule stability and minus-end clustering. We could reproduce the features of early stages of spindle assembly from twelve different experimental perturbations and predict eight additional perturbations. With its ability to characterize and predict chromosome individualization, this model can help deepen our understanding of spindle assembly. Video S1 Video S1 Simulation of early meiotic spindle assembly, simplified model. Default simulation with the first model (left). Same simulation, showing also HSET (orange) and Eg5 (yellow) bound to MTs (right). Microtubules are in green, DNA beads in blue, aMTOCs in red, total time is 900 s. Video S2 Video S2 Variation of HSET quantity, simplified model. Simulations with inhibited HSET (HSET-, left), normal level (Ctrl, middle) and over-expressed level (HSET+, right). Microtubules are in green, DNA beads in blue, aMTOCs in red, total time is 900 s. Video S3 Video S3 Simulation of early meiotic spindle assembly, extended model. Default simulation with the second model (left). Same simulation, showing also NuMA (purple) and HURP (brown) bound to MTs (right). Microtubules are in green, DNA beads in blue, aMTOCs in red, total time is 900 s. Video S4 Video S4 HSET over-expression elongates the spindle, extended model. Simulations with normal level of HSET (Ctrl, left) and with HSET over-expressed (HSET+, right). Video S5 Video S5 Different morphologies of the system, extended model. (1st column) inverted aster (Eg5+, HSET-), (2nd) MT-ball (Ctrl values), (3rd) elongated spindle (HSET+), (4th) aster (HSET++). Microtubules are in green, DNA beads in blue, aMTOCs in red, total time is 900 s. Video S6 Video S6 Simulation predictions of perturbations with the extended model. Examples of predicted perturbations : (Left) Early Eg5, (Middle) HURP+ and (Right) Mtstab+. Microtubules are in green, DNA beads in blue, aMTOCs in red, total time is 900 s. Video S7 Video S7 Chromosomes individualization, extended model. DNA beads (blue) movement during the simulations for 3 different levels of HSET : (Left) HSET inhibited (HSET-), (Middle) default value (Ctrl) and (Right) HSET over-expressed (HSET+).