Research
Research Concept
The “Cell Morphodynamics” group studies how cells develop their complex shape. We particularly focus on the mechanisms that underlie the organization of dynamic, fibrous structures that are collectively called the cytoskeleton. To gain insight into those mechanisms, we first identify key system components via screening technologies. We then interrogate causalities between those components by combining acute activity perturbation and live-cell imaging. On the basis of those experiments, we build mathematical models of the spatio-temporal system dynamics, which help us to generate new, testable hypotheses.
Current Research
Self-organization of cytoskeletal dynamics
The emergence of cell shape can be perceived as a self-organizing process, in which dynamic, local interactions between molecules lead to pattern formation at the scale of cells. The cytoskeleton takes an important role in this process, due to its ability to translate patterns of signal network activity into patterns of intracellular forces to shape the cell. In our studies, we find that the cytoskeleton does not only transduce patterns, but is instead a central component of pattern formation based on reciprocal interplay with its regulators.
Spatio-temporal organization of cell contraction: "A sense of touch for individual cells"
In the context of our studies on cell contraction, we uncovered a self-organizing mechanism that leads to the spontaneous emergence of local pulses and propagating waves of cell contraction and of the cytoskeletal regulator Rho (Video 1) [1,2]. Our experimental analysis showed that Rho amplifies its own activity by recruiting its activator GEF-H1 and that it inhibits its activity via time-delayed activation of the molecular motor myosin and associated RhoGAPs. Furthermore, activity dynamics are modulated by matrix elasticity, showing that extracellular mechanical cues are coupled with the signal network that generates cell contraction pulses. Thus, cells use such cell contraction pulses to locally squeeze the plasma membrane and to probe the elasticity of their surroundings, and they use this information to modulate their behavior. Individual cells therefore have a sense of touch that uses an active probing mechanism that is based on the local, subcellular control of signal network activity.
Video 1: Propagation of self-amplified and self-inhibited activity that controls the contraction of the plasma membrane of cells. Here, the signal molecule is the small GTPase Rho, which can exist in an active or inactive state. Specifically, Rho regulates cell contraction by activation of a molecular motor called myosin. The video shows a time-lapse of a single, human cancer cell. Bright and warm colors represent high activity levels of Rho.
More recently, we combined acute optogenetic perturbations and monitoring of signal network activity responses to derive the reaction-diffusion system that generates pulses and waves of cell contraction [2]. Quantitative experimental and theoretical investigations of this system revealed that the cytosolic concentration and diffusion of the Rho activator GEF-H1 is a critical parameter, that controls Rho activity patterns and how they are modulated by mechanical inputs [2] (Figure 1).
Relevant Literature
[1] Graessl M, Koch J, Calderon A, Kamps D, Banerjee S, Mazel T, Schulze N, Jungkurth JK, Patwardhan R, Solouk D, Hampe N, Hoffmann B, Dehmelt L, Nalbant P (2017).
An excitable Rho GTPase signaling network generates dynamic subcellular contraction patterns.
J Cell Biol 21(14):5311-6.
doi: 10.1083/jcb.201706052.
[2] Kamps D, Koch J, Juma VO, Campillo-Funollet E, Graessl M, Banerjee S, Mazel T, Chen X, Wu YW, Portet S, Madzvamuse A, Nalbant P, Dehmelt L, (2020).
Optogenetic Tuning Reveals Rho Amplification-Dependent Dynamics of a Cell Contraction Signal Network.
Cell Reports 33(9), 108467
Acute perturbation and activity measurements in living cells
To uncover mechanisms, how cellular structures are organized in space and time, methods are required that enable direct monitoring and acute perturbation of key regulators. To reach this goal, we developed novel generic approaches to simultaneously analyze and modulate biochemical reactions inside living cells.
Protein interaction arrays in living cells
In particular, relations between multiple protein reactions have to be measured simultaneously inside individual cells to untangle complex signal networks. However, current technologies to analyze protein reactions in cells are limited by the small number of markers that can be distinguished via microscopy. To break this barrier, we developed miniaturized protein arrays that allow simultaneous monitoring of multiple protein interactions inside individual living cells (Figure 2) [3]. We are currently applying this technology to study signal networks that control cell shape changes.
Figure 2: Protein arrays inside living cells. Bait presenting artificial receptor constructs (bait-PARCs) transfer an antibody surface pattern into an ordered array of intracellular bait proteins. The interaction of a labeled prey protein with multiple bait proteins is monitored inside living cells via microscopy.
Relevant Literature
[2] Gandor S, Reisewitz S, Venkatachalapathy M, Arrabito G, Reibner M, Schröder H, Ruf K, Niemeyer CM, Bastiaens PI, Dehmelt L (2013). A protein-interaction array inside a living cell. Angew Chem Int Ed Engl 52(18):4790-4.
doi: 10.1002/anie.201209127.
"Molecular Activity Painting": Switch-like, light-controlled perturbations inside living cells
To induce acute and prolonged perturbations of protein activities in the plasma membrane we developed methods based on chemically-induced dimerization and photochemically-induced targeting to immobilized artificial receptors to directly “paint” stable network perturbations in living cells (Video 2) [4]. To combine those perturbations with activity measurements, we developed TIRF-based methods to measure the activity of the major Rho GTPases Rac1, Cdc42 and RhoA. Using these tools, we directly investigated perturbation response relationships in the spatio-temporal processing of cell contractility signaling.
Video 2: Molecular activity painting of the letter “N” via ~1µm wide lines of the Rho activitor GEF-H1 (left panel). Plasma membrane localization of GEF-H1 induced the new formation of dynamic, myosin-based contractile structures (middle panel). Right panel: combined channels.
Relevant Literature
[3] Chen X, Venkatachalapathy M, Kamps D, Weigel S, Kumar R, Orlich M, Garrecht R, Hirtz M, Niemeyer CM, Wu YW, Dehmelt L. (2017). "Molecular-Activity Painting": Switch-like, Light-Controlled Perturbations inside Living Cells. Angew Chem Int Ed Engl 21(14):5311-6.
doi: 10.1002/anie.201611432
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Location & approach
The campus of TU Dortmund University is located close to interstate junction Dortmund West, where the Sauerlandlinie A 45 (Frankfurt-Dortmund) crosses the Ruhrschnellweg B 1 / A 40. The best interstate exit to take from A 45 is "Dortmund-Eichlinghofen" (closer to Campus Süd), and from B 1 / A 40 "Dortmund-Dorstfeld" (closer to Campus Nord). Signs for the university are located at both exits. Also, there is a new exit before you pass over the B 1-bridge leading into Dortmund.
To get from Campus Nord to Campus Süd by car, there is the connection via Vogelpothsweg/Baroper Straße. We recommend you leave your car on one of the parking lots at Campus Nord and use the H-Bahn (suspended monorail system), which conveniently connects the two campuses.
TU Dortmund University has its own train station ("Dortmund Universität"). From there, suburban trains (S-Bahn) leave for Dortmund main station ("Dortmund Hauptbahnhof") and Düsseldorf main station via the "Düsseldorf Airport Train Station" (take S-Bahn number 1, which leaves every 20 or 30 minutes). The university is easily reached from Bochum, Essen, Mülheim an der Ruhr and Duisburg.
You can also take the bus or subway train from Dortmund city to the university: From Dortmund main station, you can take any train bound for the Station "Stadtgarten", usually lines U41, U45, U 47 and U49. At "Stadtgarten" you switch trains and get on line U42 towards "Hombruch". Look out for the Station "An der Palmweide". From the bus stop just across the road, busses bound for TU Dortmund University leave every ten minutes (445, 447 and 462). Another option is to take the subway routes U41, U45, U47 and U49 from Dortmund main station to the stop "Dortmund Kampstraße". From there, take U43 or U44 to the stop "Dortmund Wittener Straße". Switch to bus line 447 and get off at "Dortmund Universität S".
The H-Bahn is one of the hallmarks of TU Dortmund University. There are two stations on Campus Nord. One ("Dortmund Universität S") is directly located at the suburban train stop, which connects the university directly with the city of Dortmund and the rest of the Ruhr Area. Also from this station, there are connections to the "Technologiepark" and (via Campus Süd) Eichlinghofen. The other station is located at the dining hall at Campus Nord and offers a direct connection to Campus Süd every five minutes.
The AirportExpress is a fast and convenient means of transport from Dortmund Airport (DTM) to Dortmund Central Station, taking you there in little more than 20 minutes. From Dortmund Central Station, you can continue to the university campus by interurban railway (S-Bahn). A larger range of international flight connections is offered at Düsseldorf Airport (DUS), which is about 60 kilometres away and can be directly reached by S-Bahn from the university station.
The facilities of TU Dortmund University are spread over two campuses, the larger Campus North and the smaller Campus South. Additionally, some areas of the university are located in the adjacent "Technologiepark".
Site Map of TU Dortmund University (Second Page in English).