Biology subjects

Marthiens, V.

Publications and source records attributed to Marthiens, V..

4 recordsLinked to original sources

bioRxiv2025

Brain biomechanics governs mitotic fidelity of embryonic neural progenitors

Accurate chromosome segregation is essential to maintain genetic stability and prevent the onset of diseases such as developmental disorders, infertility, and cancer. While many intrinsic factors and processes involved in mitosis have been extensively characterized, less is known about how extrinsic factors and tissue properties contribute to mitotic fidelity. In this study, using both in vivo and ex vivo systems, in combination with pharmacological perturbations and high-resolution microscopy, we investigated mitosis in apical radial glial (aRG) cells--the primary neural progenitors in the developing mammalian brain. We found that the high cell density typical of early neurogenic stages enhances microtubule polymerization rates from the spindle poles, thereby influencing chromosome segregation. Mechanistically, our results indicate that cortical actin and elevated cortical tension function as sensors of biomechanical stress during mitosis. These findings identify biomechanics as a threat to mitotic fidelity in the embryonic brain.

cell biology↗

bioRxiv2025

Mitotic slippage causes nuclear instability in polyploid cells

Whole-genome duplication (WGD), leading to polyploidy can arise in physiological and pathological contexts1-5. WGD can occur via non-canonical cell cycles such as mitotic slippage, cytokinesis failure or endoreplication1,3. Whether the routes to WGD influence the behaviour of the resulting polyploid cells remains unclear. Here, we compared these routes under both physiological and non-physiological conditions. Remarkably, only mitotic slippage led to widespread nuclear abnormalities defined by highly variable nuclear deformations that we termed nuclear instability. Mechanistically, we found that these nuclei were softer - due to high levels of histone 3 phosphorylation in G1 altering chromatin compaction - and thus more vulnerable to microtubule-driven deformations. The resulting nuclear instability leads to local nuclear reorganisation and changes in 3D genome organisation impacting ultimately gene expression. Importantly, we observed similar nuclear instability in megakaryocytes, which are physiological polyploid cells that we show here to be generated by mitotic slippage, providing a molecular mechanism for their atypical nuclear architecture6,7. In striking contrast, nuclear shape was stable in different physiological polyploid cells generated by cytokinesis failure and endoreplication. Overall, our findings highlight that the route towards WGD matters and that mitotic slippage uniquely destabilizes nuclear architecture, with implications for both physiology and disease.

cell biology↗

bioRxiv2019

CELL CYCLE ASYNCHRONY GENERATES DNA DAMAGE AT MITOTIC ENTRY IN POLYPLOID CELLS

Polyploidy arises from the gain of complete chromosomes sets [1] and is known to promote cancer genome evolution. Recent evidence suggests that a large proportion of human tumours experience whole genome duplications (WGDs), which might favour the generation of highly abnormal karyotypes within a short time frame, rather than in a stepwise manner [2-6]. However, the molecular mechanisms linking whole genome duplication to genetic instability remain poorly understood. Further, possible mechanisms responsible for rapid genome reshuffling have not been described yet. Using repeated cytokinesis failure to induce polyploidization of Drosophila neural stem cells (NSCs, also called neuroblasts - NBs), we investigated the consequences of polyploidy in vivo. Here, we show that polyploid NSCs accumulate high levels of chromosome instability. Surprisingly, we found that DNA damage is generated in a subset of nuclei of polyploid NBs during mitosis, in an asymmetric manner. Importantly, our observations in flies were confirmed in mouse NSCs (mNSCs) after acute cytokinesis inhibition. Interestingly, DNA damage occurs in nuclei that were not ready to enter mitosis but were forced to do so when exposed to the mitotic environment of neighbouring nuclei within the same cell. Additionally, we found that polyploid cells are cell cycle asynchronous and forcing cell cycle synchronization is sufficient to lower the levels of DNA damage generated during mitosis. Overall, this work supports a model in which DNA damage at mitotic entry can generate a mutated genetic landscape that contributes to the onset of genetic instability.

cell biology↗

bioRxiv2018

Gene editing can generate fragile bivalents in mouse oocytes

Mouse female meiotic spindles assemble from acentriolar MTOCs (aMTOCs) that fragment into discrete foci. These are further sorted and clustered to form spindle poles, thus providing balanced forces for faithful chromosome segregation. To assess the impact of aMTOCs biogenesis on spindle assembly, we genetically induced their precocious fragmentation in mouse oocytes using conditional overexpression of Plk4, a master MTOC regulator. Excessive microtubule nucleation from these fragmented aMTOCs accelerated spindle assembly dynamics. Prematurely formed spindles promoted the breakage of three different fragilized bivalents, generated by the presence of recombined Lox P sites. Reducing the density of microtubules diminished the extent of chromosome breakage. Thus, improper spindle forces can lead to widely described yet unexplained chromosomal structural anomalies with disruptive consequences on the ability of the gamete to transmit an uncorrupted genome.

cell biology↗