Baek, K., and Schulman, B.A.
Nat Chem Biol, 2019, [Epub ahead of print].
doi: 10.1038/s41589-019-0414-3
Molecular glue concept solidifies
Molecular-glue-mediated proximity-induced degradation now allows unprecedented therapeutic targeting of previously undruggable proteins. Structures showing how aryl-sulfonamides mediate recruitment of the splicing factor RBM39 to the E3 CRL4DCAF15 broaden the mechanistic principles by which molecular glues target ubiquitylation.
Glock, P., Brauns, F., Halatek, J., Frey, E., and Schwille, P.
Elife 8, 2019.
doi: 10.7554/eLife.48646
Design of biochemical pattern forming systems from minimal motifs
Although molecular self-organization and pattern formation are key features of life, only very few pattern-forming biochemical systems have been identified that can be reconstituted and studied in vitro under defined conditions. A systematic understanding of the underlying mechanisms is often hampered by multiple interactions, conformational flexibility and other complex features of the pattern forming proteins. Because of its compositional simplicity of only two proteins and a membrane, the MinDE system from Escherichia coli has in the past years been invaluable for deciphering the mechanisms of spatiotemporal self-organization in cells. Here we explored the potential of reducing the complexity of this system even further, by identifying key functional motifs in the effector MinE that could be used to design pattern formation from scratch. In a combined approach of experiment and quantitative modeling, we show that starting from a minimal MinE-MinD interaction motif, pattern formation can be obtained by adding either dimerization or membrane-binding motifs. Moreover, we show that the pathways underlying pattern formation are recruitment-driven cytosolic cycling of MinE and recombination of membrane-bound MinE, and that these differ in their in vivo phenomenology.
Congratulations on your PhD!Silvia Martinelli
Effect of stress on protein homeostasis mediated by FKBP51 as a possible mechanism underlying stress-related psychiatric disorders
RG: Mathias V. Schmidt / Elisabeth Binder
Andrea Cosolo
Patterning of tissue stress responses by JNK and JAK/STAT
RG: Anne-Kathrin Classen
Kist, A.M., and Portugues, R.
Cell Rep, 2019, 29, 659-670.e653.
doi: 10.1016/j.celrep.2019.09.024
Optomotor Swimming in Larval Zebrafish Is Driven by Global Whole-Field Visual Motion and Local Light-Dark Transitions
Stabilizing gaze and position within an environment constitutes an important task for the nervous system of many animals. The optomotor response (OMR) is a reflexive behavior, present across many species, in which animals move in the direction of perceived whole-field visual motion, therefore stabilizing themselves with respect to the visual environment. Although the OMR has been extensively used to probe visuomotor neuronal circuitry, the exact visual cues that elicit the behavior remain unidentified. In this study, we use larval zebrafish to identify spatiotemporal visual features that robustly elicit forward OMR swimming. These cues consist of a local, forward-moving, off edge together with on/off symmetric, similarly directed, global motion. Imaging experiments reveal neural units specifically activated by the forward-moving light-dark transition. We conclude that the OMR is driven not just by whole-field motion but by the interplay between global and local visual stimuli, where the latter exhibits a strong light-dark asymmetry.
Alkmini Papadopoulou
An in vitro and in vivo study on the function of Signal Peptide Peptidase-Like 2c and 3
RG: Christian Haass / Regina Fluhrer
Kashammer, L., Saathoff, J.H., Lammens, K., Gut, F., Bartho, J., Alt, A., Kessler, B., and Hopfner, K.P.
Mol Cell, 2019, [Epub ahead of print].
doi: 10.1016/j.molcel.2019.07.035
Mechanism of DNA End Sensing and Processing by the Mre11-Rad50 Complex
DNA double-strand breaks (DSBs) threaten genome stability throughout life and are linked to tumorigenesis in humans. To initiate DSB repair by end joining or homologous recombination, the Mre11-nuclease Rad50-ATPase complex detects and processes diverse and obstructed DNA ends, but a structural mechanism is still lacking. Here we report cryo-EM structures of the E. coli Mre11-Rad50 homolog SbcCD in resting and DNA-bound cutting states. In the resting state, Mre11's nuclease is blocked by ATP-Rad50, and the Rad50 coiled coils appear flexible. Upon DNA binding, the two coiled coils zip up into a rod and, together with the Rad50 nucleotide-binding domains, form a clamp around dsDNA. Mre11 moves to the side of Rad50, binds the DNA end, and assembles a DNA cutting channel for the nuclease reactions. The structures reveal how Mre11-Rad50 can detect and process diverse DNA ends and uncover a clamping and gating function for the coiled coils.
Congratulations on your PhD!Markus Höpfler
Slx5/Slx8-dependent Ubiquitin Hotspots on Chromatin Contribute to Stress Tolerance in Saccharomyces Cerevisiae
RG: Stefan Jentsch
Andreas Kist
Cerebellar and Sensory Contributions to the Optomotor Response in Larval Zebrafish
RG: Ruben Portugues
Gehrlach, D.A., Dolensek, N., Klein, A.S., Roy Chowdhury, R., Matthys, A., Junghanel, M., Gaitanos, T.N., Podgornik, A., Black, T.D., Reddy Vaka, N., Conzelmann, K.K., and Gogolla, N.
Nat Neurosci, 2019, 22, 1424-1437.
(IMPRS-LS students are in bold)
doi: 10.1038/s41593-019-0469-1
Aversive state processing in the posterior insular cortex
Triggering behavioral adaptation upon the detection of adversity is crucial for survival. The insular cortex has been suggested to process emotions and homeostatic signals, but how the insular cortex detects internal states and mediates behavioral adaptation is poorly understood. By combining data from fiber photometry, optogenetics, awake two-photon calcium imaging and comprehensive whole-brain viral tracings, we here uncover a role for the posterior insula in processing aversive sensory stimuli and emotional and bodily states, as well as in exerting prominent top-down modulation of ongoing behaviors in mice. By employing projection-specific optogenetics, we describe an insula-to-central amygdala pathway to mediate anxiety-related behaviors, while an independent nucleus accumbens-projecting pathway regulates feeding upon changes in bodily state. Together, our data support a model in which the posterior insular cortex can shift behavioral strategies upon the detection of aversive internal states, providing a new entry point to understand how alterations in insula circuitry may contribute to neuropsychiatric conditions.
La Chioma, A., Bonhoeffer, T., and Hubener, M.
Curr Biol, 2019, 29, 2954-2960 e2955.
doi: 10.1016/j.cub.2019.07.037
Area-Specific Mapping of Binocular Disparity across Mouse Visual Cortex
Depth perception is a fundamental feature of many visual systems across species. It is relevant for crucial behaviors, like spatial orientation, prey capture, and predator detection. Binocular disparity, the difference between left and right eye images, is a powerful cue for depth perception, as it depends on an object's distance from the observer [1,2]. In primates, neurons sensitive to binocular disparity are found throughout most of the visual cortex, with distinct disparity tuning properties across primary and higher visual areas, suggesting specific roles of different higher areas for depth perception [1-3]. Mouse primary visual cortex (V1) has been shown to contain disparity-tuned neurons, similar to those found in other mammals [4,5], but it is unknown how binocular disparity is processed beyond V1 and whether it is differentially represented in higher areas. Beyond V1, higher-order, lateromedial (LM) and rostrolateral (RL) areas contain the largest representation of the binocular visual field [6,7], making them candidate areas for investigating downstream processing of binocular disparity in mouse visual cortex. In turn, comparison of disparity tuning across different mouse visual areas might help delineating their functional specializations, which are not well understood. We find clear differences in neurons' preferred disparities across areas, suggesting that higher visual area RL is specialized for encoding visual stimuli very close to the mouse. Moreover, disparity preference is related to visual field elevation, likely reflecting an adaptation to natural image statistics. Our results reveal ethologically relevant areal specializations for binocular disparity processing across mouse visual cortex.
Balaji, R., Weichselberger, V., and Classen, A.K.
Development, 2019, 146.
doi: 10.1242/dev.171256
Response of epithelial cell and tissue shape to external forces in vivo
How actomyosin generates forces at epithelial adherens junctions has been extensively studied. However, less is known about how a balance between internal and external forces establishes epithelial cell, tissue and organ shape. We used the Drosophila egg chamber to investigate how contractility at adherens junctions in the follicle epithelium is modulated to accommodate and resist forces arising from the growing germ line. We found that between stages 6 and 9, adherens junction tension in the post-mitotic epithelium decreases, suggesting that the junctional network relaxes to accommodate germline growth. At that time, a prominent medial Myosin II network coupled to corrugating adherens junctions develops. Local enrichment of medial Myosin II in main body follicle cells resists germline-derived forces, thus constraining apical areas and, consequently, cuboidal cell shapes at stage 9. At the tissue and organ level, local reinforcement of medial junction architecture ensures the timely contact of main body cells with the expanding oocyte and imposes circumferential constraints on the germ line guiding egg elongation. Our study provides insight into how adherens junction tension promotes cell and tissue shape transitions while integrating the growth and shape of an internally enclosed structure in vivo.