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Christian Eggeling, Alf Honigmann
Closing the gap: The approach of optical and computational microscopy to uncover biomembrane organization.
Biochim Biophys Acta, 1858(10) 2558-2568 (2016)
PubMed   

Biological membranes are complex composites of lipids, proteins and sugars, which catalyze a myriad of vital cellular reactions in a spatiotemporal tightly controlled manner. Our understanding of the organization principles of biomembranes is limited mainly by the challenge to measure distributions and interactions of lipids and proteins within the complex environment of living cells. With the recent advent of super-resolution optical microscopy (or nanoscopy) one now has approached the molecular scale regime with non-invasive live cell fluorescence observation techniques. Since in silico molecular dynamics (MD) simulation techniques are also improving to study larger and more complex systems we can now start to integrate live-cell and in silico experiments to develop a deeper understanding of biomembranes. In this review we summarize recent progress to measure lipid-protein interactions in living cells and give examples how MD simulations can complement and upgrade the experimental data. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Róg.
@article{Eggeling6580,
author={Christian Eggeling, Alf Honigmann},
title={Closing the gap: The approach of optical and computational microscopy to uncover biomembrane organization.},
journal={Biochimica et biophysica acta},
volume={1858},
issue ={10},
pages={2558--2568},
year=2016
}

Katrin Peschke, Martin Achleitner, Kathrin Frenzel, Alexander Gerbaulet, Servi Remzi Ada, Nicolas Zeller, Stefan Lienenklaus, Mathias Lesche, Claire Poulet, Ronald Naumann, Andreas Dahl, Ursula Ravens, Claudia Günther, Werner Müller, Klaus-Peter Knobeloch, Marco Prinz, Axel Roers, Rayk Behrendt
Loss of Trex1 in Dendritic Cells Is Sufficient To Trigger Systemic Autoimmunity.
J Immunol, 197(6) 2157-2166 (2016)
PubMed   

Defects of the intracellular enzyme 3' repair exonuclease 1 (Trex1) cause the rare autoimmune condition Aicardi-Goutières syndrome and are associated with systemic lupus erythematosus. Trex1(-/-) mice develop type I IFN-driven autoimmunity, resulting from activation of the cytoplasmic DNA sensor cyclic GMP-AMP synthase by a nucleic acid substrate of Trex1 that remains unknown. To identify cell types responsible for initiation of autoimmunity, we generated conditional Trex1 knockout mice. Loss of Trex1 in dendritic cells was sufficient to cause IFN release and autoimmunity, whereas Trex1-deficient keratinocytes and microglia produced IFN but did not induce inflammation. In contrast, B cells, cardiomyocytes, neurons, and astrocytes did not show any detectable response to the inactivation of Trex1. Thus, individual cell types differentially respond to the loss of Trex1, and Trex1 expression in dendritic cells is essential to prevent breakdown of self-tolerance ensuing from aberrant detection of endogenous DNA.
@article{Peschke6623,
author={Katrin Peschke, Martin Achleitner, Kathrin Frenzel, Alexander Gerbaulet, Servi Remzi Ada, Nicolas Zeller, Stefan Lienenklaus, Mathias Lesche, Claire Poulet, Ronald Naumann, Andreas Dahl, Ursula Ravens, Claudia Günther, Werner Müller, Klaus-Peter Knobeloch, Marco Prinz, Axel Roers, Rayk Behrendt},
title={Loss of Trex1 in Dendritic Cells Is Sufficient To Trigger Systemic Autoimmunity.},
journal={Journal of immunology (Baltimore, Md. : 1950)},
volume={197},
issue ={6},
pages={2157--2166},
year=2016
}

Shambaditya Saha, Christoph A. Weber, Marco Nousch, Omar Adame-Arana, Carsten Hoege, Marco Y Hein, Erin Osborne-Nishimura, J. Mahamid, Marcus Jahnel, Louise Jawerth, Andrei Pozniakovski, Christian R. Eckmann, Frank Jülicher, Anthony Hyman
Polar Positioning of Phase-Separated Liquid Compartments in Cells Regulated by an mRNA Competition Mechanism.
Cell, 166(6) 1572-1584 (2016)
PubMed   

P granules are non-membrane-bound RNA-protein compartments that are involved in germline development in C. elegans. They are liquids that condense at one end of the embryo by localized phase separation, driven by gradients of polarity proteins such as the mRNA-binding protein MEX-5. To probe how polarity proteins regulate phase separation, we combined biochemistry and theoretical modeling. We reconstitute P granule-like droplets in vitro using a single protein PGL-3. By combining in vitro reconstitution with measurements of intracellular concentrations, we show that competition between PGL-3 and MEX-5 for mRNA can regulate the formation of PGL-3 droplets. Using theory, we show that, in a MEX-5 gradient, this mRNA competition mechanism can drive a gradient of P granule assembly with similar spatial and temporal characteristics to P granule assembly in vivo. We conclude that gradients of polarity proteins can position RNP granules during development by using RNA competition to regulate local phase separation.
@article{Saha6638,
author={Shambaditya Saha, Christoph A. Weber, Marco Nousch, Omar Adame-Arana, Carsten Hoege, Marco Y Hein, Erin Osborne-Nishimura, J. Mahamid, Marcus Jahnel, Louise Jawerth, Andrei Pozniakovski, Christian R. Eckmann, Frank Jülicher, Anthony Hyman},
title={Polar Positioning of Phase-Separated Liquid Compartments in Cells Regulated by an mRNA Competition Mechanism.},
journal={Cell},
volume={166},
issue ={6},
pages={1572--1584},
year=2016
}

Oliver Wueseke, David Zwicker, Anne Schwager, Yao Liang Wong, Karen Oegema, Frank Jülicher, Anthony Hyman, Jeffrey Woodruff
Polo kinase phosphorylation determines C. elegans centrosome size and density by biasing SPD-5 toward an assembly-competent conformation.
Biol Open, Art. No. doi: 10.1242/bio.020990 (2016)
  PubMed   

Centrosomes are major microtubule-organizing centers composed of centrioles surrounded by an extensive proteinacious layer called the pericentriolar material (PCM). In C. elegans embryos, the mitotic PCM expands by Polo-kinase (PLK-1) phosphorylation-accelerated assembly of SPD-5 molecules into supramolecular scaffolds. However, how PLK-1 phosphorylation regulates SPD-5 assembly is not known. We found that a mutant version of SPD-5 that is insensitive to PLK-1 phosphorylation (SPD-5(4A)) could localize to PCM but was unable to rescue the reduction in PCM size and density when wild-type SPD-5 levels were decreased. In vitro, purified SPD-5(4A) self-assembled into functional supramolecular scaffolds over long time scales, suggesting that phosphorylation only controls the rate of SPD-5 scaffold assembly. Furthermore, the SPD-5 scaffold, once assembled, remained intact and supported microtubule nucleation in the absence of PLK-1 activity in vivo We conclude that Polo Kinase is required for rapid assembly of the PCM scaffold but not for scaffold maintenance or function. Based on this idea, we developed a theoretical model that adequately predicted PCM growth rates in different mutant conditions in vivo We propose that PLK-1 phosphorylation-dependent conversion of SPD-5 into an assembly-competent form underlies PCM formation in vivo and that the rate of this conversion determines final PCM size and density.
@article{Wueseke6636,
author={Oliver Wueseke, David Zwicker, Anne Schwager, Yao Liang Wong, Karen Oegema, Frank Jülicher, Anthony Hyman, Jeffrey Woodruff},
title={Polo kinase phosphorylation determines C. elegans centrosome size and density by biasing SPD-5 toward an assembly-competent conformation.},
journal={Biology open},
volume={},
issue ={},
pages={null--null},
year=2016
}

Massimo Ganassi, Daniel Mateju, Ilaria Bigi, Laura Mediani, Ina Poser, Hyun-Ok Kate Lee, Samuel J Seguin, Federica F Morelli, Jonathan Vinet, Giuseppina Leo, Orietta Pansarasa, Cristina Cereda, Angelo Poletti, Simon Alberti, Serena Carra
A Surveillance Function of the HSPB8-BAG3-HSP70 Chaperone Complex Ensures Stress Granule Integrity and Dynamism.
Mol Cell, 63(5) 796-810 (2016)
PubMed   

Stress granules (SGs) are ribonucleoprotein complexes induced by stress. They sequester mRNAs and disassemble when the stress subsides, allowing translation restoration. In amyotrophic lateral sclerosis (ALS), aberrant SGs cannot disassemble and therefore accumulate and are degraded by autophagy. However, the molecular events causing aberrant SG formation and the molecular players regulating this transition are largely unknown. We report that defective ribosomal products (DRiPs) accumulate in SGs and promote a transition into an aberrant state that renders SGs resistant to RNase. We show that only a minor fraction of aberrant SGs is targeted by autophagy, whereas the majority disassembles in a process that requires assistance by the HSPB8-BAG3-HSP70 chaperone complex. We further demonstrate that HSPB8-BAG3-HSP70 ensures the functionality of SGs and restores proteostasis by targeting DRiPs for degradation. We propose a system of chaperone-mediated SG surveillance, or granulostasis, which regulates SG composition and dynamics and thus may play an important role in ALS.
@article{Ganassi6631,
author={Massimo Ganassi, Daniel Mateju, Ilaria Bigi, Laura Mediani, Ina Poser, Hyun-Ok Kate Lee, Samuel J Seguin, Federica F Morelli, Jonathan Vinet, Giuseppina Leo, Orietta Pansarasa, Cristina Cereda, Angelo Poletti, Simon Alberti, Serena Carra},
title={A Surveillance Function of the HSPB8-BAG3-HSP70 Chaperone Complex Ensures Stress Granule Integrity and Dynamism.},
journal={Molecular cell},
volume={63},
issue ={5},
pages={796--810},
year=2016
}

Jacqueline Tabler, Christopher P Rice, Karen J Liu, John Wallingford
A novel ciliopathic skull defect arising from excess neural crest.
Dev Biol, 417(1) 4-10 (2016)
PubMed   

The skull is essential for protecting the brain from damage, and birth defects involving disorganization of skull bones are common. However, the developmental trajectories and molecular etiologies by which many craniofacial phenotypes arise remain poorly understood. Here, we report a novel skull defect in ciliopathic Fuz mutant mice in which only a single bone pair encases the forebrain, instead of the usual paired frontal and parietal bones. Through genetic lineage analysis, we show that this defect stems from a massive expansion of the neural crest-derived frontal bone. This expansion occurs at the expense of the mesodermally-derived parietal bones, which are either severely reduced or absent. A similar, though less severe, phenotype was observed in Gli3 mutant mice, consistent with a role for Gli3 in cilia-mediated signaling. Excess crest has also been shown to drive defective palate morphogenesis in ciliopathic mice, and that defect is ameliorated by reduction of Fgf8 gene dosage. Strikingly, skull defects in Fuz mutant mice are also rescued by loss of one allele of fgf8, suggesting a potential route to therapy. In sum, this work is significant for revealing a novel skull defect with a previously un-described developmental etiology and for suggesting a common developmental origin for skull and palate defects in ciliopathies.
@article{Tabler6644,
author={Jacqueline Tabler, Christopher P Rice, Karen J Liu, John Wallingford},
title={A novel ciliopathic skull defect arising from excess neural crest.},
journal={Developmental biology},
volume={417},
issue ={1},
pages={4--10},
year=2016
}

Jochen H Weishaupt, Tony Hyman, Ivan Dikic
Common Molecular Pathways in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
Trends Mol Med, 22(9) 769-783 (2016)
PubMed   

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative diseases in which predominantly motor neurons and cerebral cortex neurons, respectively, are affected. Several novel ALS and FTD disease genes have been recently discovered, pointing toward a few overarching pathways in ALS/FTD pathogenesis. Nevertheless, a precise picture of how various cellular processes cause neuronal death, or how different routes leading to ALS and FTD are functionally connected is just emerging. Moreover, how the most recent milestone findings in the ALS/FTD field might lead to improved diagnosis and treatment is actively being explored. We highlight some of the most exciting recent topics in the field, which could potentially facilitate the identification of further links between the pathogenic ALS/FTD pathways related to autophagy, vesicle trafficking, and RNA metabolism.
@article{Weishaupt6627,
author={Jochen H Weishaupt, Tony Hyman, Ivan Dikic},
title={Common Molecular Pathways in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.},
journal={Trends in molecular medicine},
volume={22},
issue ={9},
pages={769--783},
year=2016
}

Benjamin Schmid, Wiebke Jahr, Michael Weber, Jan Huisken
Software Framework for Controlling Unsupervised Scientific Instruments.
PLoS ONE, 11(8) Art. No. e0161671 (2016)
  PubMed   

Science outreach and communication are gaining more and more importance for conveying the meaning of today's research to the general public. Public exhibitions of scientific instruments can provide hands-on experience with technical advances and their applications in the life sciences. The software of such devices, however, is oftentimes not appropriate for this purpose. In this study, we describe a software framework and the necessary computer configuration that is well suited for exposing a complex self-built and software-controlled instrument such as a microscope to laymen under limited supervision, e.g. in museums or schools. We identify several aspects that must be met by such software, and we describe a design that can simultaneously be used to control either (i) a fully functional instrument in a robust and fail-safe manner, (ii) an instrument that has low-cost or only partially working hardware attached for illustration purposes or (iii) a completely virtual instrument without hardware attached. We describe how to assess the educational success of such a device, how to monitor its operation and how to facilitate its maintenance. The introduced concepts are illustrated using our software to control eduSPIM, a fluorescent light sheet microscope that we are currently exhibiting in a technical museum.
@article{Schmid6610,
author={Benjamin Schmid, Wiebke Jahr, Michael Weber, Jan Huisken},
title={Software Framework for Controlling Unsupervised Scientific Instruments.},
journal={PloS one},
volume={11},
issue ={8},
pages={null--null},
year=2016
}

M Gai, Federico Bianchi, Cristiana Vagnoni, Fiammetta Vernì, Silvia Bonaccorsi, Selina Pasquero, G E Berto, F Sgrò, A M A Chiotto, Laura Annaratone, Anna Sapino, Anna Bergo, Nicoletta Landsberger, Jacqueline Bond, Wieland B. Huttner, F Di Cunto
ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules.
EMBO Rep, Art. No. doi: 10.15252/embr.201541823 (2016)
PubMed   

Correct orientation of cell division is considered an important factor for the achievement of normal brain size, as mutations in genes that affect this process are among the leading causes of microcephaly. Abnormal spindle orientation is associated with reduction of the neuronal progenitor symmetric divisions, premature cell cycle exit, and reduced neurogenesis. This mechanism has been involved in microcephaly resulting from mutation of ASPM, the most frequently affected gene in autosomal recessive human primary microcephaly (MCPH), but it is presently unknown how ASPM regulates spindle orientation. In this report, we show that ASPM may control spindle positioning by interacting with citron kinase (CITK), a protein whose loss is also responsible for severe microcephaly in mammals. We show that the absence of CITK leads to abnormal spindle orientation in mammals and insects. In mouse cortical development, this phenotype correlates with increased production of basal progenitors. ASPM is required to recruit CITK at the spindle, and CITK overexpression rescues ASPM phenotype. ASPM and CITK affect the organization of astral microtubules (MT), and low doses of MT-stabilizing drug revert the spindle orientation phenotype produced by their knockdown. Finally, CITK regulates both astral-MT nucleation and stability. Our results provide a functional link between two established microcephaly proteins.
@article{Gai6625,
author={M Gai, Federico Bianchi, Cristiana Vagnoni, Fiammetta Vernì, Silvia Bonaccorsi, Selina Pasquero, G E Berto, F Sgrò, A M A Chiotto, Laura Annaratone, Anna Sapino, Anna Bergo, Nicoletta Landsberger, Jacqueline Bond, Wieland B. Huttner, F Di Cunto},
title={ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules.},
journal={EMBO reports},
volume={},
issue ={},
pages={null--null},
year=2016
}

Simon Alberti, Anthony Hyman
Are aberrant phase transitions a driver of cellular aging?
Bioessays, Art. No. doi: 10.1002/bies.201600042 (2016)
  PubMed   

Why do cells age? Recent advances show that the cytoplasm is organized into many membrane-less compartments via a process known as phase separation, which ensures spatiotemporal control over diffusion-limited biochemical reactions. Although phase separation is a powerful mechanism to organize biochemical reactions, it comes with the trade-off that it is extremely sensitive to changes in physical-chemical parameters, such as protein concentration, pH, or cellular energy levels. Here, we highlight recent findings showing that age-related neurodegenerative diseases are linked to aberrant phase transitions in neurons. We discuss how these aberrant phase transitions could be tied to a failure to maintain physiological physical-chemical conditions. We generalize this idea to suggest that the process of cellular aging involves a progressive loss of the organization of phase-separated compartments in the cytoplasm.
@article{Alberti6626,
author={Simon Alberti, Anthony Hyman},
title={Are aberrant phase transitions a driver of cellular aging?},
journal={BioEssays : news and reviews in molecular, cellular and developmental biology},
volume={},
issue ={},
pages={null--null},
year=2016
}