Microtubule-Dependent Orchestration of Centriole Amplification in Brain Multiciliated Cells

Kernekoncepter

Microtubules organize the pericentrosomal nest from which procentrioles emerge, retain deuterosomes in a focused area, promote their maturation, and assist in the collective migration of centrioles to the apical membrane during multiciliated cell differentiation.

Resumé

The content describes the role of microtubules in orchestrating the process of centriole amplification in brain multiciliated cells (MCCs). Key insights include:

Centriole amplification begins in a pericentrosomal "nest" composed of centrin, pericentrin, and the deuterosome protein Deup1. This nest is organized by microtubules.

Deup1 exhibits oscillatory dynamics towards the centrosome, suggesting a physical link between deuterosomes and the centrosome. Disrupting microtubules leads to dispersion of the Deup1 cloud and deuterosomes.

As amplification progresses, procentrioles acquire microtubules and convert into multiple microtubule organizing centers (MTOCs), losing the centrosome's dominance. This "centriole-to-centrosome" conversion is marked by recruitment of the PCM protein pericentrin and the kinase Plk1.

Microtubules are required for the migration of procentriole-loaded deuterosomes to the nuclear membrane and their subsequent disengagement and collective apical migration. Disrupting microtubules impairs this process, leading to incomplete centriole disengagement.

The study reveals new insights into the spatial and temporal orchestration of centriole amplification, highlighting the central role of microtubules in organizing this process.

Statistik

Procentrioles without microtubules are located closer to parent centrioles compared to procentrioles with microtubules.
Procentriole length and width increase with distance from parent centrioles during amplification.
Chronic nocodazole treatment reduces the proportion of cells in the disengagement (D) stage and leads to incomplete centriole disengagement.

Citater

"Microtubules organize the centrosome nest from which procentriole-loaded deuterosomes emerge and keep them in a restricted area around the centrosome during A-phase, through typical centrosomal oscillations."
"From the G-stage, tens of centrosome-like structures are present in MCC progenitors, participating in microtubule cytoskeleton organization."
"Microtubules are required for procentriole attachment to the nuclear membrane and efficient disengagement."

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Microtubule-dependent orchestration of centriole amplification in brain multiciliated cells

by Boudjema,A.-... kl. www.biorxiv.org 02-12-2024

https://www.biorxiv.org/content/10.1101/2024.02.09.579615v1

Dybere Forespørgsler

How do the molecular mechanisms underlying the "centriole-to-centrosome" conversion in multiciliated cells compare to the G2-M transition in cycling cells?

In multiciliated cells, the "centriole-to-centrosome" conversion during the A-to-G transition shares similarities with the G2-to-M transition in cycling cells. Both processes involve the recruitment of Plk1 and PCM proteins to procentrioles, leading to the formation of multiple microtubule-organizing centers (MTOCs). This conversion allows procentrioles to nucleate microtubules and participate in cytoskeleton organization. In cycling cells, the G2-to-M transition involves the acquisition of PCM by centrioles, enabling them to function as MTOCs for spindle organization during mitosis. The recruitment of Plk1 and PCM proteins to procentrioles in multiciliated cells and centrioles in cycling cells marks the transition from centriole amplification to maturation, preparing them for their respective functions in ciliogenesis and cell division.

What are the potential implications of impaired centriole disengagement on multiciliated cell function and ciliopathies?

Impaired centriole disengagement in multiciliated cells can have significant implications on cell function and contribute to the development of ciliopathies. Efficient centriole disengagement is crucial for the proper distribution of centrioles around the nucleus and subsequent migration to the apical surface for ciliogenesis. Failure to disengage centrioles from deuterosomes can lead to incomplete ciliation, affecting the cell's ability to generate functional motile cilia required for fluid flow circulation. This can disrupt normal physiological processes such as mucociliary clearance in the respiratory tract and cerebrospinal fluid circulation in the brain, leading to respiratory and neurological disorders associated with ciliopathies.

Could the microtubule-dependent orchestration of centriole amplification be exploited to control centriole number in other cellular contexts, such as cancer cells?

The microtubule-dependent orchestration of centriole amplification observed in multiciliated cells could potentially be exploited to control centriole number in other cellular contexts, including cancer cells. In cancer cells, abnormal centriole amplification can lead to genomic instability and promote tumor formation. By understanding the role of microtubules in organizing centriole amplification, novel therapeutic strategies could be developed to modulate centriole duplication and limit centriole number in cancer cells. Targeting the microtubule network or key regulators involved in centriole biogenesis could offer a potential approach to inhibit excessive centriole amplification in cancer cells, thereby reducing genomic instability and potentially slowing down tumor progression.