Pécréaux Group Research

How does a robust and adaptive cell division emerge from the numerous interactions of involved players?

The lab aims to address this question using a multi-disciplinary approach.
We will account for the emergence of properties like robustness to perturbations (either for good, in development, or bad in cancerous cells able to divide despite their accumulated defects) or adaptability to protein evolution [See: Riche et al. 2013]. 

Microtubules dynamics contribute to regulating the pulling forces undergone by the mitotic spindle. This contributes to its positioning, elongation and rocking. When the spindle is far from its final posterior position, few microtubules reach the area where force generators are active, precluding a premature pulling (A). This is a positional switch upon the forces exerted on the spindle [Riche et al. JCB 2013, Bouvrais et al., In prep.]. A-B. Schematic representations of nematode embryos showing (A) overcentration and slightly anteriorly displaced spindle formation during prophase, (B) spindle at early anaphase, at oscillations onset. Red and Blue disks represent anterior and posterior centrosomes, respectively. From them, emanate microtubules (MTs) that either reach the cortex (cell periphery) and find an active force generator (black thick lines) either are too short or reach an inactive region of the cortex (MTs depicted by thin green lines). Inactive forces generators are represented in light green, engaged ones (pulling on a MT) in dark green. Astral microtubules in purple sector reach the cortex in the active region (green), which is limited by the LET-99 domain [Krueger et al. 2009]. Spindle is schematized with microtubules as black thin lines and chromosomes in light blue. Vertical dashed line marks the geometric middle of the antero-posterior axis. © Jacques PECREAUX / IGDR

To do so, the relevant level is, rather than the protein or protein complex level, the mechanism that can be seen as a (broad) pathway, which is well-conserved thorough evolution. This is a network of interacting players well approached by the statistical physics. Such a change of paradigm is highly promising for future applications in cancer therapy. 

In contrast to previous “biochemical” systems biology approaches, we focus on mechanics, in vivo. Indeed, mitosis involves regulation of forces that position the spindle, separate sister chromatids, etc. We benefit from the growing corpus of in vitro experiments shedding light on the properties and roles of microfilaments and molecular motors. We investigate not only the dynamics of components but also pseudo-balance in forces, for example the slow elongation of the spindle (out-of-equilibrium in the words of physics). This pseudo-balance provides an advantage in adaptability [See: Prost et al., 2015].

To do so, we develop microscopy and image processing tools to quantify the dynamics in vivo using C. elegans as a model organism and we model it (using mathematical equations and numerical simulations) using out-of-equilibrium statistical physics.

Indeed, we aim to build a multi-scale model, using out-of-equilibrium statistical physics, linking the molecular details to the “macroscopic” mechanisms, completed by numerical simulations (virtual cell division) to test the role of each component in silico; this could serve as a predictive tool for fundamental and applied research (testing/screening of drugs e.g.). To ease the applicability of our recapitulating models, we started testing our models on cultured human cells (leukemia).

This figure depicts the main activities of the lab. In periphery appear contributions of connected research. © Jacques PECREAUX / IGDR

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