Centrosome Age Impact on Spindle Symmetry in Cell Division

Core Concepts

Centrosome age disrupts spindle symmetry via microtubule nucleation.

Abstract

The study explores how centrosome age influences spindle symmetry in human epithelial and fibroblastic cells. Centrosomes of different ages lead to subtle spindle asymmetries, affecting daughter cell sizes. Pericentrin, Cdk5Rap2, and γ-tubulin accumulate preferentially on old centrosomes, impacting microtubule nucleation. The presence of daughter centrioles dampens the asymmetry induced by grandmother centrioles. Depletion of pericentrin or TPX2 restores spindle symmetry, highlighting their role in breaking spindle symmetry based on centrosome age. Additionally, Plk1 binding to cenexin drives spindle size and polar chromosome asymmetries.

Stats

For 2:2 cells SAI = 1.4% ± 6.2%, n=133 cells, p = 0.0104; for 1:1 cells = 4.1 ± 7.3%, n=96 cells, p <0.0001; for 1:0 cells = 19.3% ± 11.2%, n=111 cells, p <0.0001; and for 0:0 cells = 0.9% ± 13.3%, n=77 cells, p = 0.54 in one-sample t-tests. Means of (G) pericentrin and (H) TPX2 fluorescence intensity at spindle poles in siCtrl (n=44 cells), siPCNT (n=45 cells) and siTPX2-treated (n=30 cells) RPE1 GFP-centrin1 cells showed significant differences (p < 0.0001). Relative TPX2 distribution means of 3% ± 6.5%, n=36 cells, p = 0.0210 in WT RPE1 GFP-centrin1 vs., mScarlet-cenexin S796A with a mean of -0% ±5%, n=55cells, p = .5917.

Quotes

"Old centrosomes have a higher microtubule nucleation capacity." "Pericentrin contributes to TPX2 recruitment at spindle poles." "The cenexin-bound pool of Plk1 breaks spindle symmetry."

Key Insights Distilled From

Centrosome age breaks spindle size symmetry even in “symmetrically” dividing cells

by Thomas,A., M... at www.biorxiv.org 09-15-2023

https://www.biorxiv.org/content/10.1101/2023.09.15.557935v1

Deeper Inquiries

How does the presence of daughter centrioles affect overall cell division dynamics

The presence of daughter centrioles can significantly impact overall cell division dynamics. In the context described, it was observed that cells lacking daughter centrioles displayed a stronger spindle asymmetry than those with intact daughter centrioles. This suggests that daughter centrioles play a role in dampening the symmetry breaking imposed by centrosome age. Daughter centrioles are typically considered immature; however, under certain conditions, they can organize spindle poles and recruit essential proteins like γ-tubulin. In terms of cell division dynamics, the presence of daughter centrioles influences spindle size symmetry and asymmetric cell daughter sizes. When daughter centrioles are absent or dysfunctional, as seen in 1:0 cells in the study, there is a higher likelihood of asymmetric spindles and subsequently unevenly sized daughter cells. This highlights the importance of proper functioning daughter centrioles in maintaining balanced cell division processes.

What implications could the findings have on cancer research where abnormal cell division is common

The findings regarding spindle asymmetry and its molecular mechanisms could have significant implications for cancer research where abnormal cell division is common. Cancer cells often exhibit dysregulated mitotic processes leading to chromosomal instability and aberrant cell divisions. Understanding how factors such as pericentrin, Cdk5Rap2, γ-tubulin, TPX2, TACC3, Kif2A, katanin influence spindle size symmetry can provide valuable insights into cancer progression. Abnormalities in these proteins could contribute to faulty mitotic spindles and unequal chromosome segregation during cell division - characteristics commonly observed in cancer cells. By targeting these specific molecules involved in regulating microtubule nucleation or dynamics at spindle poles (as shown by their correlation with spindle asymmetry), researchers may develop novel therapeutic strategies to disrupt cancerous cell divisions and potentially inhibit tumor growth. Additionally, understanding how cenexin-bound Plk1 controls both spindle size and polar chromosome asymmetries opens up avenues for targeted therapies aimed at disrupting this interaction specifically within cancer cells exhibiting uncontrolled proliferation rates due to defective mitosis.

How might understanding the molecular mechanisms behind spindle asymmetry contribute to developing targeted therapies

Understanding the molecular mechanisms behind spindle asymmetry has great potential for contributing to the development of targeted therapies for various diseases including cancers characterized by abnormal cell division processes. Targeted Drug Development: Insights into how proteins like pericentrin/Cdk5Rap2/γ-tubulin regulate microtubule nucleation at differentially aged centrosomes can guide drug development efforts focused on disrupting these interactions selectively within diseased cells while sparing healthy ones. Precision Medicine: By identifying key players like TPX2 that drive asymmetric spindles irrespective of centrism age or TACC3 which might be more relevant when dealing with non-centrosomal microtubule organizing centers (e.g., oocytes), personalized treatment strategies based on individual protein expression profiles could be developed. Therapeutic Targets: Targeting specific components involved in controlling spindle size symmetry offers a promising approach for developing therapeutics aimed at restoring normal cellular division patterns disrupted in diseases like cancer where uncontrolled proliferation is prevalent. By honing in on these intricate molecular pathways governing mitotic processes through detailed studies as outlined above researchers may uncover new druggable targets paving the way for more effective treatments tailored towards correcting aberrant cellular behavior seen across various pathological conditions including cancers characterized by faulty mitosis.