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Peter Dobrowolski, Melina Fischer, Ronald Naumann
Novel insights into the genetic background of genetically modified mice.
Transgenic Res., 1-1 (2018)
PubMed Source   

Unclear or misclassified genetic background of laboratory rodents or a lack of strain awareness causes a number of difficulties in performing or reproducing scientific experiments. Until now, genetic differentiation between strains and substrains of inbred mice has been a challenge. We have developed a screening method for analyzing inbred strains regarding their genetic background. It is based on 240 highly informative short tandem repeat (STR) markers covering the 19 autosomes as well as X and Y chromosomes. Combination of analysis results for presence of known C57BL/6 substrain-specific mutations together with autosomal STR markers and the Y-chromosomal STR-haplotype provides a comprehensive snapshot of the genetic background of mice. In this study, the genetic background of 72 mouse lines obtained from 18 scientific institutions in Germany and Austria was determined. By analyzing only 3 individuals per genetically modified line it was possible to detect mixed genetic backgrounds frequently. In several lines presence of a mispairing Y chromosome was detected. At least every second genetically modified line displayed a mixed genetic background which could lead to unexpected and non-reproducible results, irrespective of the investigated gene of interest.
@article{Dobrowolski7107,
author={Peter Dobrowolski, Melina Fischer, Ronald Naumann},
title={Novel insights into the genetic background of genetically modified mice.},
journal={Transgenic research},
volume={},
pages={1--1},
year=2018
}

Shovamayee Maharana, Jie Wang, Dimitrios Papadopoulos, Doris Richter, Andrei I. Pozniakovsky, Ina Poser, Marc Bickle, Sandra Rizk, Jordina Guillén-Boixet, Titus Franzmann, Marcus Jahnel, Lara Marrone, Young-Tae Chang, Jared Sterneckert, Pavel Tomancak, Anthony Hyman, Simon Alberti
RNA buffers the phase separation behavior of prion-like RNA binding proteins.
Science, 1-1 (2018)
PubMed Source   

Prion-like RNA binding proteins (RBPs) such as TDP-43 or FUS are largely soluble in the nucleus, but form solid pathological aggregates when mislocalized to the cytoplasm. What keeps these proteins soluble in the nucleus and promotes aggregation in the cytoplasm is still unknown. We report here that RNA critically regulates the phase behavior of prion-like RBPs. Low RNA/protein ratios promote phase separation into liquid droplets, whereas high ratios prevent droplet formation in vitro. Reduction of nuclear RNA levels or genetic ablation of RNA binding causes excessive phase separation and the formation of cytotoxic solid-like assemblies in cells. We propose that the nucleus is a buffered system in which high RNA concentrations keep RBPs soluble. Changes in RNA levels or RNA binding abilities of RBPs cause aberrant phase transitions.
@article{Maharana7106,
author={Shovamayee Maharana, Jie Wang, Dimitrios Papadopoulos, Doris Richter, Andrei I. Pozniakovsky, Ina Poser, Marc Bickle, Sandra Rizk, Jordina Guillén-Boixet, Titus Franzmann, Marcus Jahnel, Lara Marrone, Young-Tae Chang, Jared Sterneckert, Pavel Tomancak, Anthony Hyman, Simon Alberti},
title={RNA buffers the phase separation behavior of prion-like RNA binding proteins.},
journal={Science (New York, N.Y.)},
volume={},
pages={1--1},
year=2018
}

Matthäus Mittasch, Anatol Fritsch, Michael Nestler, Juan M Iglesias Artola, Kaushikaram Subramanian, Heike Petzold, Mrityunjoy Kar, Axel Voigt, Moritz Kreysing
Active gelation breaks time-reversal-symmetry of mitotic chromosome mechanics
bioRxiv, Art. No. 296566 (2018)
Source   

In cell division, mitosis is the phase in which duplicated sets of chromosomes are mechanically aligned to form the metaphase plate before being segregated in two daughter cells. Irreversibility is a hallmark of this process, despite the fundamental laws of Newtonian mechanics being time symmetric. Here we show experimentally that mitotic chromosomes receive the arrow of time by time-reversal-symmetry breaking of the underlying mechanics in prometaphase. By optically inducing hydrodynamic flows within prophase nuclei, we find that duplicated chromatid pairs initially form a fluid suspension in the nucleoplasm: although showing little motion on their own, condensed chromosomes are free to move through the nucleus in a time-reversible manner. Actively probing chromosome mobility further in time, we find that this viscous suspension of chromatin transitions into a gel after nuclear breakdown. This gel state, in which chromosomes cannot be moved by flows, persists even when chromosomes start moving to form the metaphase plate. Complemented by minimal reconstitution experiments, our active intra-nuclear micro-rheology reveals time-reversal-symmetry breaking of chromosome mechanics to be caused by the transition from a purely fluid suspension into an active gel.
@article{Mittasch7102,
author={Matthäus Mittasch, Anatol Fritsch, Michael Nestler, Juan M Iglesias Artola, Kaushikaram Subramanian, Heike Petzold, Mrityunjoy Kar, Axel Voigt, Moritz Kreysing},
title={Active gelation breaks time-reversal-symmetry of mitotic chromosome mechanics},
journal={bioRxiv},
volume={},
pages={null--null},
year=2018
}

Alina Neunkirchner, Bernhard Kratzer, Cordula Köhler, Ursula Smole, Lukas F Mager, Klaus G Schmetterer, Doris Trapin, Victoria Leb-Reichl, Edward Rosloniec, Ronald Naumann, Lukas Kenner, Beatrice Jahn-Schmid, Barbara Bohle, Rudolf Valenta, Winfried F Pickl
Genetic restriction of antigen-presentation dictates allergic sensitization and disease in humanized mice.
EBioMedicine, 1-1 (2018)
PubMed Source   

Immunoglobulin(Ig)E-associated allergies result from misguided immune responses against innocuous antigens. CD4+ T lymphocytes are critical for initiating and perpetuating that process, yet the crucial factors determining whether an individual becomes sensitized towards a given allergen remain largely unknown.
@article{Neunkirchner7108,
author={Alina Neunkirchner, Bernhard Kratzer, Cordula Köhler, Ursula Smole, Lukas F Mager, Klaus G Schmetterer, Doris Trapin, Victoria Leb-Reichl, Edward Rosloniec, Ronald Naumann, Lukas Kenner, Beatrice Jahn-Schmid, Barbara Bohle, Rudolf Valenta, Winfried F Pickl},
title={Genetic restriction of antigen-presentation dictates allergic sensitization and disease in humanized mice.},
journal={EBioMedicine},
volume={},
pages={1--1},
year=2018
}

Stefano Lazzarano, Marek Kučka, João P L Castro, Ronald Naumann, Paloma Medina, Michael N C Fletcher, Rebecka Wombacher, Joost Gribnau, Tino Hochepied, Marc Van Montagu, Claude Libert, Yingguang Frank Chan
Genetic mapping of species differences via in vitro crosses in mouse embryonic stem cells.
Proc Natl Acad Sci U.S.A., 115(14) 3680-3685 (2018)
PubMed Source   

Discovering the genetic changes underlying species differences is a central goal in evolutionary genetics. However, hybrid crosses between species in mammals often suffer from hybrid sterility, greatly complicating genetic mapping of trait variation across species. Here, we describe a simple, robust, and transgene-free technique to generate "in vitro crosses" in hybrid mouse embryonic stem (ES) cells by inducing random mitotic cross-overs with the drug ML216, which inhibits the DNA helicase Bloom syndrome (BLM). Starting with an interspecific F1 hybrid ES cell line between theMus musculuslaboratory mouse andMus spretus(∼1.5 million years of divergence), we mapped the genetic basis of drug resistance to the antimetabolite tioguanine to a single region containing hypoxanthine-guanine phosphoribosyltransferase (Hprt) in as few as 21 d through "flow mapping" by coupling in vitro crosses with fluorescence-activated cell sorting (FACS). We also show how our platform can enable direct study of developmental variation by rederiving embryos with contribution from the recombinant ES cell lines. We demonstrate how in vitro crosses can overcome major bottlenecks in mouse complex trait genetics and address fundamental questions in evolutionary biology that are otherwise intractable through traditional breeding due to high cost, small litter sizes, and/or hybrid sterility. In doing so, we describe an experimental platform toward studying evolutionary systems biology in mouse and potentially in human and other mammals, including cross-species hybrids.
@article{Lazzarano7092,
author={Stefano Lazzarano, Marek Kučka, João P L Castro, Ronald Naumann, Paloma Medina, Michael N C Fletcher, Rebecka Wombacher, Joost Gribnau, Tino Hochepied, Marc Van Montagu, Claude Libert, Yingguang Frank Chan},
title={Genetic mapping of species differences via in vitro crosses in mouse embryonic stem cells.},
journal={Proceedings of the National Academy of Sciences of the United States of America},
volume={115},
issue ={14},
pages={3680--3685},
year=2018
}

Dominic B Bernkopf, Kowcee Jalal, Martina Brückner, Karl X Knaup, Marc Gentzel, Alexandra Schambony, Jürgen Behrens
Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling.
J Cell Biol, 217(4) 1383-1394 (2018)
PubMed Source   

Mitochondrial abundance is dynamically regulated and was previously shown to be increased by Wnt/β-catenin signaling. Pgam5 is a mitochondrial phosphatase which is cleaved by the rhomboid protease presenilin-associated rhomboid-like protein (PARL) and released from membranes after mitochondrial stress. In this study, we show that Pgam5 interacts with the Wnt pathway component axin in the cytosol, blocks axin-mediated β-catenin degradation, and increases β-catenin levels and β-catenin-dependent transcription. Pgam5 stabilized β-catenin by inducing its dephosphorylation in an axin-dependent manner. Mitochondrial stress triggered by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) treatment led to cytosolic release of endogenous Pgam5 and subsequent dephosphorylation of β-catenin, which was strongly diminished in Pgam5 and PARL knockout cells. Similarly, hypoxic stress generated cytosolic Pgam5 and led to stabilization of β-catenin, which was abolished by Pgam5 knockout. Cells stably expressing cytosolic Pgam5 exhibit elevated β-catenin levels and increased mitochondrial numbers. Our study reveals a novel mechanism by which damaged mitochondria might induce replenishment of the mitochondrial pool by cell-intrinsic activation of Wnt signaling via the Pgam5-β-catenin axis.
@article{Bernkopf7103,
author={Dominic B Bernkopf, Kowcee Jalal, Martina Brückner, Karl X Knaup, Marc Gentzel, Alexandra Schambony, Jürgen Behrens},
title={Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling.},
journal={The Journal of cell biology},
volume={217},
issue ={4},
pages={1383--1394},
year=2018
}

Edgar Boczek, Simon Alberti
One domain fits all: Using disordered regions to sequester misfolded proteins.
J Cell Biol, 217(4) 1173-1175 (2018)
PubMed Source   

Small heat shock proteins (sHsps) are adenosine triphosphate-independent chaperones that protect cells from misfolded proteins. In this issue, Grousl et al. (2018.J. Cell Biol.https://doi.org/10.1083/jcb.201708116) show that the yeast sHsp Hsp42 uses a prion-like intrinsically disordered domain to bind and sequester misfolded proteins in protein deposition sites.
@article{Boczek7099,
author={Edgar Boczek, Simon Alberti},
title={One domain fits all: Using disordered regions to sequester misfolded proteins.},
journal={The Journal of cell biology},
volume={217},
issue ={4},
pages={1173--1175},
year=2018
}

Carsten Wolff, Jean-Yves Tinevez, Tobias Pietzsch, Evangelia Stamataki, Benjamin Harich, Léo Guignard, Stephan Preibisch, Spencer Shorte, Patrick Keller, Pavel Tomancak, Anastasios Pavlopoulos
Multi-view light-sheet imaging and tracking with the MaMuT software reveals the cell lineage of a direct developing arthropod limb.
Elife, 7 Art. No. e34410 (2018)
PubMed Source   

During development, coordinated cell behaviors orchestrate tissue and organ morphogenesis. Detailed descriptions of cell lineages and behaviors provide a powerful framework to elucidate the mechanisms of morphogenesis. To study the cellular basis of limb development, we imaged transgenic fluorescently-labeled embryos from the crustaceanParhyale hawaiensiswith multi-view light-sheet microscopy at high spatiotemporal resolution over several days of embryogenesis. The cell lineage of outgrowing thoracic limbs was reconstructed at single-cell resolution with new software called Massive Multi-view Tracker (MaMuT).In silicoclonal analyses suggested that the early limb primordium becomes subdivided into anterior-posterior and dorsal-ventral compartments whose boundaries intersect at the distal tip of the growing limb. Limb-bud formation is associated with spatial modulation of cell proliferation, while limb elongation is also driven by preferential orientation of cell divisions along the proximal-distal growth axis. Cellular reconstructions were predictive of the expression patterns of limb development genes including the BMP morphogen Decapentaplegic.
@article{Wolff7094,
author={Carsten Wolff, Jean-Yves Tinevez, Tobias Pietzsch, Evangelia Stamataki, Benjamin Harich, Léo Guignard, Stephan Preibisch, Spencer Shorte, Patrick Keller, Pavel Tomancak, Anastasios Pavlopoulos},
title={Multi-view light-sheet imaging and tracking with the MaMuT software reveals the cell lineage of a direct developing arthropod limb.},
journal={eLife},
volume={7},
pages={null--null},
year=2018
}

Steven Boeynaems, Simon Alberti, Nicolas L Fawzi, Tanja Mittag, Magdalini Polymenidou, Frederic Rousseau, Joost Schymkowitz, James Shorter, Benjamin Wolozin, Ludo Van Den Bosch, Peter Tompa, Monika Fuxreiter
Protein Phase Separation: A New Phase in Cell Biology.
Trends Cell Biol., Art. No. doi: 10.1016/j.tcb.2018.02.004 (2018)
PubMed Source   

Cellular compartments and organelles organize biological matter. Most well-known organelles are separated by a membrane boundary from their surrounding milieu. There are also many so-called membraneless organelles and recent studies suggest that these organelles, which are supramolecular assemblies of proteins and RNA molecules, form via protein phase separation. Recent discoveries have shed light on the molecular properties, formation, regulation, and function of membraneless organelles. A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.
@article{null7100,
author={Steven Boeynaems, Simon Alberti, Nicolas L Fawzi, Tanja Mittag, Magdalini Polymenidou, Frederic Rousseau, Joost Schymkowitz, James Shorter, Benjamin Wolozin, Ludo Van Den Bosch, Peter Tompa, Monika Fuxreiter},
title={Protein Phase Separation: A New Phase in Cell Biology.},
journal={Trends in cell biology},
volume={},
pages={null--null},
year=2018
}

Virag Sharma, Nikolai Hecker, Juliana Roscito, Leo Foerster, Bjorn Langer, Michael Hiller
A genomics approach reveals insights into the importance of gene losses for mammalian adaptations.
Nat Commun, 9(1) Art. No. 1215 (2018)
  PubMed Source   

Identifying the genomic changes that underlie phenotypic adaptations is a key challenge in evolutionary biology and genomics. Loss of protein-coding genes is one type of genomic change with the potential to affect phenotypic evolution. Here, we develop a genomics approach to accurately detect gene losses and investigate their importance for adaptive evolution in mammals. We discover a number of gene losses that likely contributed to morphological, physiological, and metabolic adaptations in aquatic and flying mammals. These gene losses shed light on possible molecular and cellular mechanisms that underlie these adaptive phenotypes. In addition, we show that gene loss events that occur as a consequence of relaxed selection following adaptation provide novel insights into species' biology. Our results suggest that gene loss is an evolutionary mechanism for adaptation that may be more widespread than previously anticipated. Hence, investigating gene losses has great potential to reveal the genomic basis underlying macroevolutionary changes.
@article{Sharma7077,
author={Virag Sharma, Nikolai Hecker, Juliana Roscito, Leo Foerster, Bjorn Langer, Michael Hiller},
title={A genomics approach reveals insights into the importance of gene losses for mammalian adaptations.},
journal={Nature communications},
volume={9},
issue ={1},
pages={null--null},
year=2018
}