Double-checking chromosome segregation

Maiato, Hélder; Silva, Sonia Cristina Pinela da

doi:10.1083/jcb.202301106

Cited by 17 publications

(4 citation statements)

References 181 publications

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“…It may allow cells to react to erroneous kinetochoremicrotubule attachments that cannot be detected by the spindle assembly checkpoint and do not extend mitotic timing, such as merotelic kinetochore-microtubule attachments (one kinetochore bound by microtubules from both spindle poles; ( 52)). Such merotelic attachments are often transiently lagging in anaphase and rapidly corrected by Aurora B (23,53,54); such a surveillance system would allow to detect those transient lagging chromosomes that are not immediately corrected and potentially prevent the proliferation of cells having experienced such a segregation error. Indeed, lagging chromosomes can contribute to chromosome compaction and nuclear architecture defects in the absence of aneuploidy and impair post-natal growth in mice (55).…”

Section: Discussionmentioning

confidence: 99%

Transient lagging chromosomes cause primary microcephaly

Doria,

Ivanova,

Thomas

et al. 2024

Preprint

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Primary microcephaly is caused by the depletion of neuronal progenitor cells during brain development, resulting in reduced brain size and impaired cognitive abilities. It arises due to recessive loss-of-function mutations of cell division genes, that are thought to cause neuronal progenitor loss either because of aneuploidy-driven apoptosis, spindle orientation defects, or prolonged mitotic timing. Loss of the two most frequently impaired microcephaly genes, WDR62 and ASPM, elicits, however, none of these phenotypes in human cells. Instead, their loss slows down poleward microtubule flux and results in transient lagging chromosomes in anaphase. Whether these defects cause primary microcephaly is, however, unknown. Here we show that slower poleward microtubule flux rates lead to transient lagging anaphase chromosomes that elicit an Aurora-B dependent activation of 53BP1 and the p53-target p21, impairing cell proliferation. Co-depletion of CAMSAP1, an inhibitor of microtubule depolymerization at spindle poles, restores normal poleward flux rates, suppresses the lagging chromosomes, silences 53BP1 and p21 activation, and allows normal cell proliferation in WDR62-depleted cells. In Drosophila melanogaster larvae knock-down of the CAMSAP1 ortholog Patronin suppresses the small brain, the neuroblast depletion, and the impaired cognitive phenotype associated with WDR62 loss. We thus postulate that poleward microtubule flux defects in neuronal progenitor cells drive primary microcephaly due to the activation of 53BP1 and p21 in response to transient lagging chromosomes in anaphase. Since loss of most cell division genes associated with primary microcephaly can lead to such transient lagging chromosomes, we speculate that they might represent a common cause of this disease.

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Section: Discussionmentioning

confidence: 99%

Transient lagging chromosomes cause primary microcephaly

Doria,

Ivanova,

Thomas

et al. 2024

Preprint

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“…The correction mechanisms, which are activated on unstable or erroneous microtubule kinetochore connections, require the activity of chromosomal passenger complex (CPC) and, specifically, Aurora B kinase, which disengage the incorrect connections by phosphorylation of the kinetochore components [63,64]. The correction mechanisms are active, even after SAC is turned off [65][66][67], which provides the opportunity for the correction of improper attachments even during anaphase.…”

Section: The Assembly Of the Spindle Is Under Surveillancementioning

confidence: 99%

Chromosome Division in Early Embryos—Is Everything under Control? And Is the Cell Size Important?

Horakova,

Konecna,

Anger

2024

IJMS

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Chromosome segregation in female germ cells and early embryonic blastomeres is known to be highly prone to errors. The resulting aneuploidy is therefore the most frequent cause of termination of early development and embryo loss in mammals. And in specific cases, when the aneuploidy is actually compatible with embryonic and fetal development, it leads to severe developmental disorders. The main surveillance mechanism, which is essential for the fidelity of chromosome segregation, is the Spindle Assembly Checkpoint (SAC). And although all eukaryotic cells carry genes required for SAC, it is not clear whether this pathway is active in all cell types, including blastomeres of early embryos. In this review, we will summarize and discuss the recent progress in our understanding of the mechanisms controlling chromosome segregation and how they might work in embryos and mammalian embryos in particular. Our conclusion from the current literature is that the early mammalian embryos show limited capabilities to react to chromosome segregation defects, which might, at least partially, explain the widespread problem of aneuploidy during the early development in mammals.

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“…On the other hand, the non-amphitelic attachments are erroneous and promote aneuploidy. During the spindle assembly process, several 'error correction' mechanisms specifically destabilize the erroneous attachments so that only the correct amphitelic attachments prevail (recently reviewed in [51]). Although our present model does not include the correction of erroneous attachments, we asked the following question: without the intervention of any error correction mechanism, what is the relative fraction of amphitelic attachments, when all the chromosomes are captured?…”

Section: Chmentioning

confidence: 99%

Microtubule search-and-capture model evaluates the effect of chromosomal volume conservation on spindle assembly during mitosis

Nayak

Chatterjee

Paul

2023

Preprint

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Variation in the chromosome numbers can arise from the erroneous mitosis or fusion and fission of chromosomes. While the mitotic errors lead to an increase or decrease in the overall chromosomal substance in the daughter cells, fission and fusion keep this conserved. Variations in chromosome numbers are assumed to be a crucial driver of speciation. E.g., members of the muntjac species are known to have very different karyotypes with the chromosome numbers varying from 2n=70+3B in the brown brocket deer to 2n=46 in the Chinese muntjac and 2n=6/7 in the Indian muntjac. The chromosomal content in the nucleus of these closely related mammals is roughly the same and various chromosome fusion and fission pathways have been suggested as the evolution process of these karyotypes. Similar trends can also be found in lepidoptera and yeast species which show a wide variation of chromosome numbers. The effect of chromosome number variation in mitosis is still not properly understood. We computationally investigate the effect of conservation of the total chromosomal substance on the spindle assembly during prometaphase. Our results suggest that chromosomal fusion pathways aid the microtubule-driven Search and Capture of the kinetochore in cells with monocentric chromosomes. We further report a comparative analysis of the altered positioning and percentage of amphitelic captures in respect of chromosomal volume partitioning.

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Double-checking chromosome segregation

Cited by 17 publications

References 181 publications

Transient lagging chromosomes cause primary microcephaly

Transient lagging chromosomes cause primary microcephaly

Chromosome Division in Early Embryos—Is Everything under Control? And Is the Cell Size Important?

Microtubule search-and-capture model evaluates the effect of chromosomal volume conservation on spindle assembly during mitosis

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