Revealing how Microtubule Mechanics contribute to cell division Robustness (MM2R)

Project title

Revealing how Microtubule Mechanics contribute to cell division Robustness (MM2R)

Call for expression of interest description

The Marie S. Curie Postdoctoral Fellowship (MSCA-PF) programme is a highly prestigious renowned EU-funded scheme. It offers talented scientists a unique chance to set up 2-year research and training projects with the support of a supervising team. Besides providing an attractive grant, it represents a major opportunity to boost the career of promising researchers.

The Institute of Genetics and Development of Rennes (IGDR, Team “Cell Division Reverse Engineering”) is thus looking for excellent postdoctoral researchers with an international profile to write a persuasive proposal to apply for a Marie S. Curie Postdoctoral Fellowship grant in 2023 (deadline of the EU call set on 13 September 2023). The topic and research team presented below have been identified in this regard.

Main Research Field

• Life Sciences (LIF)

Research sub- field(s)

Cellular and molecular biology / Biophysics / System biology

Keywords

Cell division robustness / Spindle positioning / Chromosome segregation / Caenorhabditis elegans embryo / Human culture cells / Microtubule mechanics / Microtubule flexural rigidity /Advanced optical microscopy / Image processing and data analysis.

Research project description

Context:

In contrast to the past view of microtubules ‘as passive support’ for cargo transport or transmitting force, our lab and others revealed the key role of their dynamics during cell division. We showed that they contribute to the mitotic-spindle robust positioning in the C. elegans one-cell embryo through a mechano-sensing pathway [1,2], likely calling for regulating microtubule rigidity [2,3].

Indeed, on top of biochemical processes already well investigated, it appears that mechanical aspects play an important role in cell division. For instance, it is now established that tension at the kinetochores – the specialised structure connecting microtubules and chromosomes – is required to ensure a correct attachment and thus a faithful partitioning of the chromosomes. However, the microtubule bending rigidity received limited attention, although we foresee that it contributes significantly to cell division [3].

Previous studies in neuronal cells showed that microtubule rigidity could be regulated by microtubule bundling, protofilaments coupling, post-translational modifications (directly or by modifying the microtubule affinity for particular microtubule-associated proteins). We envision that some of these mechanisms also exist in dividing cells. They are likely combined with additional factors that may favor or contribute to locally curve the microtubules like the lattice defects or the mechanical coupling with the elastic environment. Alternatively, repaired lattice defects could act as rigid patches along the microtubule lattice, locally preventing microtubule flexion/buckling. Similarly, microtubule coupling with the other cytoskeletal filaments could increase microtubule flexural rigidity.

Objective:

Determining whether microtubule mechanics participate in cell division fidelity and robustness.

By robustness, we mean that cell division occurs despite chromosomal defects (e.g. aneuploidy and tetraploidy), suggesting some adaptations likely involving cell mechanics. For instance, we wonder whether an optimal microtubule-rigidity range may exist and permit cell division adapting, especially to chromosomal attachment defects.

Approaches:

The Postdoctoral fellow will work on Caenorhabditis elegans one-cell embryo, which is an established model for cell division. He will benefit from home-made advanced biophysical tools, which provide unique data about the regulation of the spindle external forces and the spindle internal mechanics.

The findings in the nematode may be then transferred to human cells, both healthy and defective ones to challenge cell adapting capacities.

References:

1. Bouvrais, H., Chesneau, L., Pastezeur, S., Fairbrass, D., Delattre, M., and Pécréaux, J. “Microtubule feedback and LET-99-dependent control of pulling forces ensure robust spindle position.” Biophysical Journal, 2018.
2. Bouvrais, H., Chesneau, L., Le Cunff, Y., Fairbrass, D., Soler, N., Pastezeur, S., Pécot, T., Kervrann, C., and Pécréaux, J. “The coordination of spindle-positioning forces during the asymmetric division of the C. elegans zygote is revealed by distinct microtubule dynamics at the cortex.” EMBO Reports, 2021.
3. Pécréaux, J., Redemann, S., Alayan, Z., Mercat, B., Pastezeur, S., Garzon-Coral, C., Hyman, A.A., and Howard, J. “The mitotic spindle in the one-cell C. elegans embryo is positioned with high precision and stability.” Biophysical Journal, 2016.

Supervisor(s)

The Postdoctoral Fellow will be supervised by Hélène Bouvrais, CNRS researcher.

Dr Hélène Bouvrais short CV :

Hélène performs interdisciplinary research to investigate how microtubules contribute to cell division robustness. For that, she conducts her project-team in the lab of Jacques Pécréaux at the Institute of Genetics and Development of Rennes (IGDR). To summarise her research journey, she started in model systems for Biology and moved towards modelling of living systems, constantly performing her research in a multidisciplinary environment. Indeed, she started with a joint PhD thesis between a Danish lab (MEMPHYS – Center for Biomembrane Physics) and a French lab (ENSCR) in lipid biochemistry and membrane biophysics (6 peer-reviewed publications, rewarded with the Bretagne young researcher prize). Then, she did her first post-doctoral stay in Denmark, using for the first time the membrane model systems in the field of ecotoxicology (collaborative work, 4 peer-reviewed publications). She performed her second post-doctoral stay in France, grounded on quantifying and modelling living systems, which was the prequel of her current research project (competitive EMBO post-doctoral long- term fellowship). While this funding was in progress, she was awarded in January 2016 a CNRS permanent position. In 2022, she obtained the ANR JCJC funding to study how the microtubule mechanics contribute to a faithful cell division. She starts these investigations using the C. elegans nematode as model organism and will pursue them in human cells, with a particular interest for cancerous cells.

Three most significant publications/productions:

• [1] Bouvrais et al., “Microtubule feedback and LET-99-dependent control of pulling forces ensure robust spindle position”, Biophysical J., 115(11): 2189- 2205, 2018.
• [2] Bouvrais et al., “The coordination of spindle-positioning forces during the asymmetric division of the Caenorhabditis elegans zygote”, EMBO report, 22, e50770, 2021.
• [3] DiLiPop (Distinct Lifetime (sub)Population) analysis enabling to identify distinct dynamical behaviors — Code supporting Bouvrais et al. EMBO Reports (2021). doi: 10.5281/zenodo:4552485.

Webpage:

https://igdr.univ-rennes.fr/helene-bouvrais

Department/ Research

Pécréaux lab:

The research team, led by Jacques Pécréaux, is interested in the robustness of cell division to internal (e.g. chromosomal aberrations) and external (e.g. mechanical deformations) perturbations. This robustness is ambivalent. On the one hand, this property of cell division allows, from a unicellular embryo, the correct development of a complex and multicellular organism, such as Humans. On the other hand, this robustness allows the division of cancerous cells despite the accumulated defects (e.g. abnormal number of chromosomes) and leads to the resistance of cancer cells to anti-cancer treatments. Understanding the mechanisms of this robustness is therefore one of the research challenges in cell biology. This robustness emerges from the mechanistic interactions between many molecular actors, which are the microtubules, the motors and their regulators. A study of this robustness by the biophysical tools seems relevant, as it considers the complex network of these multiple interactions.

To address these questions, the Pécréaux lab performs multi-disciplinarily research (cell biology, biophysics, bioinformatics), combines investigations at the cellular and microscopic scales and develops original methods based on advanced image and data analysis, to access unique data, such as the DiLiPop assay. Besides, our lab, together with the TramierLab (same institute) and Inscoper, SAS (a spin-off of the labs), contributes to developing an automated microscope that feeds back image on-the-fly classification to the driving unit (roboscope). The roboscope will be particularly relevant to study human cell division, since it will permit an automated acquisition of dividing cells, avoiding chemical cell synchronising that may affect cell division robustness mechanisms.

The quality of CeDRE-team research is demonstrated by competitive grants (since 2013: 1 ANR PRCE, 1 ANR JCJC, a Plan Cancer, 2 charity-funded PhD fellowships, and the roboscope funding by the “pôle de compétitivité Images et Réseaux”), publications in high-profile journals, two patents, and selected oral presentations or invitations in meetings.

The institute:

The IGDR is Brittany's leading institute of cell and developmental biology, and genomics. It is a dynamic and expanding institute, which is internationally renowned and administratively supervised by CNRS, INSERM and University of Rennes. The institute includes 15 teams and covers a wide range of subjects in cell biology, using different model organisms (e.g. C. elegans nematode, Drosophila melanogaster, Xenopus species). The candidate will thus benefit from the research environment from other IGDR teams on related topics. The institute strongly promotes interdisciplinary approaches, particularly at the interface between physics and biology. Besides, CeDRE team is strongly involved in the scientific animation of the institute, e.g. organizing shared labmeetings (MicBioPhys for Microscopy Biology & Physics, and C. elegans related ones), thematical meetings (BIS for Biology In Silico, and MT-igdr dedicated to microtubule field), and being part of the PhD program.

Research environment in Rennes:

In Rennes, the candidate will benefit from a state-of-the-art microscopy facility (MRiC). In particular, the teams of S. Huet, M. Tramier and J. Pécréaux contribute to transferring their microscopy-related developments and are thus identified as R&D teams by the France BioImaging national infrastructure. Finally, the BIOSIT facility offers a helpdesk for image analysis.

Webpage:

For the team: https://igdr.univ-rennes.fr/en/cedre-lab For the institute: https://igdr.univ-rennes.fr/en

Location

Campus Santé de Villejean, Faculté de Médecine 2 avenue du Professeur Léon Bernard, CS 34317 35043 Rennes Cedex, France

Suggestion for interdisciplinary / intersectoral secondments and placements

Skills Requirements

The applicant should hold a PhD in biology. Proven experience in the field of cell biology and in fluorescence microscopy are a prerequisite. Prior experience in the study of microtubules or cell division and in image analysis will be considered extremely favourably, but is not mandatory. Some knowledge in genetics and some interests for biophysics and system biology would be a plus.

Fluency in English, both written and oral, is mandatory. French is not a prerequisite.

At least two publications in the field of cell biology, with one as first author, are expected.