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Stephan Grill

Motor Systems, Biophysics

Welcome to the Grill Group. We are an interdisciplinary research group working at the BIOTEC Institute of TU Dresden and the Max-Planck-Institute of Molecular Cell Biology and Genetics in Dresden.

Morphogenesis refers to the generation of form in Biology. Our group is interested in understanding the biophysical basis of morphogenesis, how an unpatterned blob of cells develops into a fully structured and formed organism. We combine theory and experiment, and investigate force generation on multiple scales. At the level of cells an tissues we study how the actomyosin cell cortex self contracts, reshapes and deforms, and how these morphogenetic activities couple to regulatory biochemical pathways. At the level of molecules we investigate force generation and movement of individual molecules of RNA polymerases in the context of gene expression and transcriptional proofreading.

Morphogenetic functions of actomyosin

Actomyosin cortex of a one cell stage C. elegans embryo cut with a pulsed UV laser along the blue line. Non-muscle-myosin 2 is visualized by GFP fluorescence (pre-ablation image in magenta, post-ablation image in green). Note that the material moves away from the line of cut (arrows), revealing that the material is under mechanical tension. Scale bar, 5 µm. Modified from Mayer et al., Nature (2010).

The generation of form in biology is characterized by reshaping, deformation and flow. The forces that drive all these processes are generated by the actomyosin cortex. We are interested in characterizing the types of mechanical activities the actomyosin cortex can produce at cell and tissue scales for driving morphogenetic events. In particular, we investigate the physical basis of polarizing cortical flow in the early stages of life of the nematode Caenorhabditis elegans. Flow results from the ability of the actomyosin cortex to ‘contract’, a feature that emerges as a consequence of many molecules interacting; individual proteins cannot do this. We use imaging techniques to measure biophysical parameters such as flow velocity and alignment, and use UV laser ablation to measure cortical tension. We describe the mechanical basis of these cell biological events in terms of novel hydrodynamic descriptions of active materials, in terms of a thin film of an active viscous fluid. We use RNAi to perturb the function of different genes to characterize how they contribute to the mechanical behavior at cellular length and time scales.  At the multicellular scale, we have also identified a crucial role for flow of actomyosin into an actomyosin ring for driving epiboly during zebrafish gastrulation.

We have recently discovered that the actomyosin cortex is able to generate torques of defined chirality, and a particular focus of our work is to understand the physical mechanisms by which active torque generation by actomyosin contributes to left/right symmetry breaking in development.

 

Mechanochemical pattern formation

Anterior (red) and posterior (magenta) PAR domains during polarity establishment in the one cell stage C. elegans zygote. Scale bar, 10 µm. Modified from Goehring et al., Science (2011).

The generation of form is characterized by a coupling between mechanical events and biochemical regulation. Regulatory pathways direct the active deformation and reshaping of cells and tissues. Components of the regulatory pathways are transported by flow and deformation arising from active mechanical processes inside cells. In some instances of morphogenetic pattern formation one can successfully decouple the biochemistry from the mechanics. This is the approach that was taken sixty years ago by Alan Turing when he started the field of reaction-diffusion, but we are learning more and more that generally this is not possible.

We have recently put forward a novel mechanism of biological pattern formation. Here,  stationary patterns in active fluids emerge because active stress gradients drive hydrodynamic flows which in turn advect the active stress regulator to counterbalance diffusive fluxes. We are investigating how this type of interplay between active mechanics and biochemical regulation leads to cell polarization. We study the establishment of cell polarity in the C. elegans zygote, a classical example of coupling of mechanical and biochemical pathways for enacting morphogenetic change. In particular, we have shed light on how cortical flow, through advection, triggers the formation of a pattern in the PAR polarity system to polarize the cell.

Micromechanics of transcription

A single molecule of RNA polymerase II walking along a DNA template in a dual trap optical tweezer. Transcription is intermittent and characterized by frequent pausing (red).

The molecular machines that generate morphogenetic forces and transcription factors that control molecular pathways need to be produced. Transcription is the first step in gene expression, and we are interested in unraveling the micro-mechanical details that underly transcription by RNA polymerases. We use single-molecule high-resolution dual-trap optical tweezers to characterize molecule-scale force generation and movement by RNA polymerases. We study the molecular events that are at the heart of transcription, and how they give rise to more general types of behaviors such as transcriptional pausing and proofreading. We make use of theoretical approaches to understand how distinct kinetic mechanisms relate biophysical modes of operation to specific cellular roles and functions. For example, we recently described how intermittent transcription dynamics ensure high transcriptional fidelity.

Selected Publications

2013
Depken, Martin; Parrondo, Juan; Grill, Stephan W.
Intermittent transcription dynamics for the rapid production of long transcripts of high fidelity.
Cell Rep., 5, no. 2, pp. 521-530, (2013)
2012
Behrndt, Martin; Salbreux, Guillaume; Campinho, Pedro; Hauschild, Robert; Oswald, Felix; Roensch, Julia; Grill, Stephan W.; Heisenberg, Carl-Philipp
Forces driving epithelial spreading in zebrafish gastrulation.
Science, 338, no. 6104, pp. 257-260, (2012)
2011
Goehring, Nathan; Trong, Philipp Khuc; Bois, Justin; Chowdhury, Debanjan; Nicola, Ernesto M; Hyman, Anthony A.; Grill, Stephan W.
Polarization of PAR Proteins by Advective Triggering of a Pattern-Forming System.
Science, 334, no. 6059, pp. 1137-1141, (2011)
Bois, Justin; Jülicher, Frank; Grill, Stephan W.
Pattern formation in active fluids
Phys. Rev. Lett., 106, no. 2, (2011)
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2010
Mayer, Mirjam; Depken, Martin; Bois, Justin; Jülicher, Frank; Grill, Stephan W.
Anisotropies in cortical tension reveal the physical basis of polarizing cortical flows.
Nature, 467, no. 7315, pp. 617-621, (2010)
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2009
Depken, Martin; Galburt, Eric A.; Grill, Stephan W.
The origin of short transcriptional pauses.
Biophys. J., 96, no. 6, pp. 2189-2193, (2009)
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2007
Galburt, Eric A.; Grill, Stephan W.; Wiedmann, Anna; Lubkowska, Lucyna; Choy, Jason; Nogales, Eva; Kashlev, Mikhail; Bustamante, Carlos
Backtracking determines the force sensitivity of RNAP II in a factor-dependent manner.
Nature, 446, no. 7137, pp. 820-823, (2007)
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2005
Grill, Stephan W.; Kruse, Karsten; Jülicher, Frank
Theory of mitotic spindle oscillations.
Phys. Rev. Lett., 94, no. 10, pp. 108104-108104, (2005)
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2003
Grill, Stephan W.; Howard, Jonathon; Schäffer, Erik; Stelzer, Ernst H K; Hyman, Anthony A.
The distribution of active force generators controls mitotic spindle position.
Science, 301, no. 5632, pp. 518-521, (2003)
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2001
Grill, Stephan W.; Gönczy, Pierre; Stelzer, Ernst H K; Hyman, Anthony A.
Polarity controls forces governing asymmetric spindle positioning in the Caenorhabditis elegans embryo.
Nature, 409, no. 6820, pp. 630-633, (2001)
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