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Mechanics of living tissue during embryo development: understanding biological observations with a mechanical model

Version française : Mécanique des tissus vivants lors du développement embryonnaire : comprendre les observations biologiques à l'aide d'un modèle mécanique
Applications are invited for a PhD position to be held at the Laboratoire Interdisciplinaire de Physique, Université Grenoble Alpes, in collaboration with the Dept. of Physiology, Development and Neuroscience, University of Cambridge.
Keywords: Biophysics, Complex fluids, Continuum mechanics, Developmental biology, Reaction-diffusion, Interdisciplinary research.
Advisors:
Jocelyn Étienne, Jocelyn.Etienne@UJF-Grenoble.fr
Guy Blanchard, gb288@cam.ac.uk
Funding: 1452 € per calendar month, funded by Laboratory of Excellence "The Engineering of Compexity".

Illustration
During the development of living organisms, large-scale movements of tissues occur to sculpt the adult form from a single fertilized egg. The mechanics of these deformations is poorly understood, although their driving forces are known to originate in the subcellular dynamics of filaments of actin proteins, which are contracted by the action of myosin, a motor-molecule. Understanding the self-organizing capacity of networks of actin and myosin and how this is controlled during development to generate appropriate form is one of the great current challenges at the interface between physics and biology. The objective of this PhD project is to work on physical models of the subcellular dynamics of these filaments, and of the resulting tissue-scale dynamics of cells, in order to understand how the molecular processes give rise to the correct morphogenetic movements.

A morphogenetic movement in which such an understanding is now possible is dorsal closure of the amnioserosa (AS) tissue of the Drosophila fruit-fly (Figure 1A). The AS is a single cell layered film, or epithelium, overlying the yolk of the fly embryo, and attached at its edges to other epithelial tissues. Over the course of two hours, the AS tissue contracts until the neighbouring tissues come together. Although much is known about what genes and molecules are necessary for this closure, much less is known about which forces are generated and how they are controlled.

Figure 1: Dorsal closure in the Drosophila fruit-fly. A Global amnioserosa (AS) tissue shape evolution over two hours. B Fluorescence microscopy image from a movie of AS development: cell junctions (magenta) and myosin (green) forming foci at cell surfaces (apices). C Schematic of the flow of a myosin focus across a cell, with associated local cell shape deformation. D Schematic of the velocity and density fields for the sub-cellular model (1st part of the PhD project). E Schematic of the shape and velocities for the tissue model (2nd part of the PhD project).
Image AS

The AS epithelium is composed of approximately 200 cells. Just under the outer membrane of every cell, long actin filaments form a network that contributes to the mechanical properties of the cell. Of particular interest is the part of this network on the apical surface of cells, that is, on the surface facing out from the embryo. Small myosin motors contract this actin network, leading ultimately to the contraction of the tissue. Remarkably, contraction occurs in cyclic pulses, with sub-cellular accumulations of actin and myosin, called foci, appearing to flow across cell apices (Figure 1B,C and movie in Fischer et al., PLoS One, 2014). Understanding the physics of these foci is the first objective of the PhD thesis. This will be achieved by coupling a classical advection-reaction-diffusion equation, to describe the evolution of the density ρ (Figure 1D), with the rheological model developed by J. Étienne (PNAS, 2015), to describe the velocity v in relation to the stress in the tissue. The resulting model will be studied both analytically in one dimension, and numerically in three dimensions, using the C++ finite element software rheolef.

Once this sub-cellular model is established, simulated and validated against detailed biological measurements, the objective is to understand the larger scale tissue dynamics (Figure 1E). Actin networks are connected from cell to cell by adhesion molecules that allow forces generated at the sub-cellular level to be transmitted to neighbouring cells. Indeed, during the process of dorsal closure, the cycles of foci formation drive deformations of the cell and of its neighbours (Blanchard et al., Development, 2010). The PhD student will take part in the development of a tissue-scale model incorporating previous findings, and will compare the mechanical behaviour that this model predicts to observed cell and tissue behaviour.


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Requirements

Applicants should have a first or upper second class degree (or equivalent) in mechanics or physics. He/she should be comfortable using both analytical and numerical approaches to analyse the behaviour of the models. The numerical resolution will be done in the finite element C++ library Rheolef (website), which specializes in nonlinear rheology problems and is co-developed by Jocelyn Étienne.

Skills required:


The student will be registered in Université Grenoble Alpes and will mostly work in Laboratoire Interdisciplinaire de Physique with advisor Jocelyn Étienne, and with Guy Blanchard who will be present for several months per year in Grenoble, France. Travel to Cambridge, UK, and Madrid where relevant experimental work is being carried out will be possible.

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The Laboratoire Interdisciplinaire de Physique is located in Grenoble.

Grenoble is the unique conjunction of a well-established university city with world-class research groups, within a breathtaking mountain landscape.

The Laboratoire was originally a Physics department, but is now highly interdisciplinary with many mechanicists, applied mathematicians and biologists working there as staff, post-docs or graduate students.

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The Department of Physiology, Development and Neuroscience at the University of Cambridge is one of the premier Departments world-wide for studying developmental biology and its dynamics.

Funding is provided within a Tec21 project. 1452 € salary per calendar month for 3 years. Health insurance is included. A paid complementary activity during the PhD, consisting of either teaching, research dissemination or valorisation, can be applied for. This complementary activity corresponds to 1/6 of the work time and increases the monthly salary to 1744 €.

Applications should include a letter detailing the motivation and relevance of the applicant's background for this particular project (max. 300 words), a full CV and the names and email addresses of three referees. Please direct enquiries to Jocelyn Étienne or Guy Blanchard, and send applications to Jocelyn.Etienne@UJF-Grenoble.fr before 31st January 2016.

Start date between 1st March and 30th September 2016.


References

Blanchard GB, Murugesu S, Adams RJ, Martinez-Arias A and Gorfinkiel N. 2010. Cytoskeletal dynamics and supra-cellular organization of cell shape fluctuations during dorsal closure. Development 137:2743-2752.

Étienne J, J. Fouchard, D. Mitrossilis, N. Bufi, P. Durand-Smet and A. Asnacios, 2015 Cells as liquid motors: Mechanosensitivity emerges from collective dynamics of actomyosin cortex. Proc. Natl. Acad. Sci. USA 112(9):2740–2745. Website.

Fischer SC, Blanchard GB, Duque J, Adams RJ, et al. 2014. Contractile and Mechanical Properties of Epithelia with Perturbed Actomyosin Dynamics. PLoS ONE 9:e95695.

Machado PF, Duque J, Etienne J, Arias AM, Blanchard GB and Gorfinkiel N. 2015. Active rheology and emergent material properties of developing epithelial tissues. BMC Biol. ``Beyond Mendel: modeling in biology'' series 13:98





Jocelyn Etienne 2015-12-18