Abstract
Chromosome congression during prometaphase culminates with the establishment of a metaphase plate, a hallmark of mitosis in metazoans. Classical views resulting from more than 100 years of research on this topic have attempted to explain chromosome congression based on the balance between opposing pulling and/or pushing forces that reach an equilibrium near the spindle equator. However, in mammalian cells, chromosome bi-orientation and force balance at kinetochores are not required for chromosome congression, whereas the mechanisms of chromosome congression are not necessarily involved in the maintenance of chromosome alignment after congression. Thus, chromosome congression and maintenance of alignment are determined by different principles. Moreover, it is now clear that not all chromosomes use the same mechanism for congressing to the spindle equator. Those chromosomes that are favorably positioned between both poles when the nuclear envelope breaks down use the so-called “direct congression” pathway in which chromosomes align after bi-orientation and the establishment of end-on kinetochore-microtubule attachments. This favors the balanced action of kinetochore pulling forces and polar ejection forces along chromosome arms that drive chromosome oscillatory movements during and after congression. The other pathway, which we call “peripheral congression”, is independent of end-on kinetochore microtubule-attachments and relies on the dominant and coordinated action of the kinetochore motors Dynein and Centromere Protein E (CENP-E) that mediate the lateral transport of peripheral chromosomes along microtubules, first towards the poles and subsequently towards the equator. How the opposite polarities of kinetochore motors are regulated in space and time to drive congression of peripheral chromosomes only now starts to be understood. This appears to be regulated by position-dependent phosphorylation of both Dynein and CENP-E and by spindle microtubule diversity by means of tubulin post-translational modifications. This so-called “tubulin code” might work as a navigation system that selectively guides kinetochore motors with opposite polarities along specific spindle microtubule populations, ultimately leading to the congression of peripheral chromosomes. We propose an integrated model of chromosome congression in mammalian cells that depends essentially on the following parameters: (1) chromosome position relative to the spindle poles after nuclear envelope breakdown; (2) establishment of stable end-on kinetochore-microtubule attachments and bi-orientation; (3) coordination between kinetochore- and arm-associated motors; and (4) spatial signatures associated with post-translational modifications of specific spindle microtubule populations. The physiological consequences of abnormal chromosome congression, as well as the therapeutic potential of inhibiting chromosome congression are also discussed.
Highlights
We propose an integrated model of chromosome congression in mammalian cells that depends essentially on the following parameters: (1) chromosome position relative to the spindle poles after nuclear envelope breakdown; (2) establishment of stable end-on kinetochore-microtubule attachments and bi-orientation; (3) coordination between kinetochore- and arm-associated motors; and (4) spatial signatures associated with post-translational modifications of specific spindle microtubule populations
The existence of two distinct motor activities operated by Dynein and Centromere Protein E (CENP-E), both localized at the kinetochore fibrous corona, but with opposite directional preferences along microtubules, posed obvious questions regarding their coordination to mediate chromosome congression
This study showed that, similar to CENP-E depletion/inhibition, attenuation of tubulin detyrosination either by inhibition of the tubulin carboxypeptidase (TCP), or by overexpression of the tubulin tyrosine ligase (TTL), prevented polar chromosomes from congressing
Summary
In preparation for cell division, two poles and an equator start to be defined by the mitotic spindle axis. At the onset of mitosis, when chromosomes start condensing and the nuclear envelope breaks down, dispersed chromosomes initiate directed movements that culminate with their position at the spindle equator before migrating to the poles after sister chromatid separation. This stochastic motion towards the equator coincides with the beginning of prometaphase and is known as “chromosome congression” (from the English “to come together”; terminology first introduced by Darlington [1]). Chromosome congression truly represents the first challenge of mitosis and culminates with the formation of a metaphase plate, a hallmark of mitosis in metazoans, and occurs in tight spatiotemporal coordination with the assembly of the mitotic spindle that mediates the microtubule-chromosome interactions required for chromosome movement
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