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Lydie Flasse, Siham Yennek, Cédric Cortijo, Irene Seijo Barandiaran, Marine R-C Kraus, Anne Grapin-Botton
Apical Restriction of the Planar Cell Polarity Component VANGL in Pancreatic Ducts Is Required to Maintain Epithelial Integrity.
Cell Rep, 31(8) Art. No. 107677 (2020)
PubMed Source   

Cell polarity is essential for the architecture and function of numerous epithelial tissues. Here, we show that apical restriction of planar cell polarity (PCP) components is necessary for the maintenance of epithelial integrity. Using the mammalian pancreas as a model, we find that components of the core PCP pathway, such as the transmembrane protein Van Gogh-like (VANGL), become apically restricted over a period of several days. Expansion of VANGL localization to the basolateral membranes of progenitors leads to their death and disruption of the epithelial integrity. VANGL basolateral expansion does not affect apico-basal polarity but acts in the cells where Vangl is mislocalized by reducing Dishevelled and its downstream target ROCK. This reduction in ROCK activity culminates in progenitor cell egression, death, and eventually pancreatic hypoplasia. Thus, precise spatiotemporal modulation of VANGL-dependent PCP signaling is crucial for proper pancreatic morphogenesis.
@article{Flasse7679,
author={Lydie Flasse, Siham Yennek, Cédric Cortijo, Irene Seijo Barandiaran, Marine R-C Kraus, Anne Grapin-Botton},
title={Apical Restriction of the Planar Cell Polarity Component VANGL in Pancreatic Ducts Is Required to Maintain Epithelial Integrity.},
journal ={Cell reports},
volume={31},
issue ={8},
pages={null--null},
year=2020
}

Deepthi Ashokkumar, Qinyu Zhang, Christian Much, Anita S. Bledau, Ronald Naumann, Dimitra Alexopoulou, Andreas Dahl, Neha Goveas, Jun Fu, Konstantinos Anastassiadis, A F Stewart, Andrea Kranz
MLL4 is required after implantation whereas MLL3 becomes essential during late gestation.
Development, Art. No. doi: 10.1242/dev.186999 (2020)
PubMed Source   

Methylation of histone 3 lysine 4 (H3K4) is a major epigenetic system associated with gene expression. In mammals there are six H3K4 methyltransferases related to yeast Set1 and fly Trithorax, including two orthologs of fly Trithorax-related: MLL3 and MLL4. Exome sequencing has documented high frequencies of MLL3 and MLL4 mutations in many types of human cancer. Despite this emerging importance, the requirements of these paralogs in mammalian development have only been incompletely reported. Here we examined the null phenotypes to establish that MLL3 is first required for lung maturation whereas MLL4 is first required for migration of the anterior visceral endoderm (AVE) that initiates gastrulation. This collective cell migration is preceded by a columnar to squamous transition in visceral endoderm cells that depends on MLL4. Furthermore, Mll4 mutants display incompletely penetrant, sex distorted, embryonic haploinsufficiency and adult heterozygous mutants show aspects of Kabuki syndrome, indicating that MLL4 action, unlike MLL3, is dosage dependent. The highly specific and discordant functions of these paralogs in mouse development argues against their action as general enhancer factors.
@article{Ashokkumar7678,
author={Deepthi Ashokkumar, Qinyu Zhang, Christian Much, Anita S. Bledau, Ronald Naumann, Dimitra Alexopoulou, Andreas Dahl, Neha Goveas, Jun Fu, Konstantinos Anastassiadis, A F Stewart, Andrea Kranz},
title={MLL4 is required after implantation whereas MLL3 becomes essential during late gestation.},
journal ={Development (Cambridge, England)},
volume={},
pages={1--1},
year=2020
}

Christiane Iserman, Christine Desroches Altamirano, Ceciel Jegers, Ulrike Friedrich, Taraneh Zarin, Anatol Fritsch, Matthäus Mittasch, Antonio Domingues, Lena Hersemann, Marcus Jahnel, Doris Richter, Ulf-Peter Guenther, Matthias W. Hentze, Alan M Moses, Anthony Hyman, Günter Kramer, Moritz Kreysing, Titus Franzmann, Simon Alberti
Condensation of Ded1p Promotes a Translational Switch from Housekeeping to Stress Protein Production.
Cell, 181(4) 818-831 (2020)
PubMed Source   

Cells sense elevated temperatures and mount an adaptive heat shock response that involves changes in gene expression, but the underlying mechanisms, particularly on the level of translation, remain unknown. Here we report that, in budding yeast, the essential translation initiation factor Ded1p undergoes heat-induced phase separation into gel-like condensates. Using ribosome profiling and an in vitro translation assay, we reveal that condensate formation inactivates Ded1p and represses translation of housekeeping mRNAs while promoting translation of stress mRNAs. Testing a variant of Ded1p with altered phase behavior as well as Ded1p homologs from diverse species, we demonstrate that Ded1p condensation is adaptive and fine-tuned to the maximum growth temperature of the respective organism. We conclude that Ded1p condensation is an integral part of an extended heat shock response that selectively represses translation of housekeeping mRNAs to promote survival under conditions of severe heat stress.
@article{Iserman7664,
author={Christiane Iserman, Christine Desroches Altamirano, Ceciel Jegers, Ulrike Friedrich, Taraneh Zarin, Anatol Fritsch, Matthäus Mittasch, Antonio Domingues, Lena Hersemann, Marcus Jahnel, Doris Richter, Ulf-Peter Guenther, Matthias W. Hentze, Alan M Moses, Anthony Hyman, Günter Kramer, Moritz Kreysing, Titus Franzmann, Simon Alberti},
title={Condensation of Ded1p Promotes a Translational Switch from Housekeeping to Stress Protein Production.},
journal ={Cell},
volume={181},
issue ={4},
pages={818--831},
year=2020
}

Katharina Kessler, Mathias J. Gerl, Silke Hornemann, Markus Damm, Christian Klose, Klaus J Petzke, Margrit Kemper, Daniela Weber, Natalia Rudovich, Tilman Grune, Kai Simons, Achim Kramer, Andreas F H Pfeiffer, Olga Pivovarova-Ramich
Shotgun Lipidomics Discovered Diurnal Regulation of Lipid Metabolism Linked to Insulin Sensitivity in Nondiabetic Men.
J. Clin. Endocrinol. Metab., 105(5) Art. No. dgz176 (2020)
PubMed Source   

Meal timing affects metabolic homeostasis and body weight, but how composition and timing of meals affect plasma lipidomics in humans is not well studied.
@article{Kessler7540,
author={Katharina Kessler, Mathias J. Gerl, Silke Hornemann, Markus Damm, Christian Klose, Klaus J Petzke, Margrit Kemper, Daniela Weber, Natalia Rudovich, Tilman Grune, Kai Simons, Achim Kramer, Andreas F H Pfeiffer, Olga Pivovarova-Ramich},
title={Shotgun Lipidomics Discovered Diurnal Regulation of Lipid Metabolism Linked to Insulin Sensitivity in Nondiabetic Men.},
journal ={The Journal of clinical endocrinology and metabolism},
volume={105},
issue ={5},
pages={null--null},
year=2020
}

Punit Saraon, Jamie Snider, Yannis Kalaidzidis, Leanne E Wybenga-Groot, Konstantin Weiss, Ankit Rai, Nikolina Radulovich, Luka Drecun, Nika Vučković, Adriana Vučetić, Victoria Wong, Brigitte Thériault, Nhu-An Pham, Jin H Park, Alessandro Datti, Jenny Wang, Shivanthy Pathmanathan, Farzaneh Aboualizadeh, Anna Lyakisheva, Zhong Yao, Yuhui Wang, Babu Joseph, Ahmed Aman, Michael F Moran, Michael Prakesch, Gennady Poda, Richard Marcellus, David Uehling, Miroslav Samaržija, Marko Jakopović, Ming-Sound Tsao, Frances A Shepherd, Adrian Sacher, Natasha Leighl, Anna Akhmanova, Rima Al-Awar, Marino Zerial, Igor Stagljar
A drug discovery platform to identify compounds that inhibit EGFR triple mutants.
Nat Chem Biol, 16(5) 577-586 (2020)
PubMed Source   

Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.
@article{Saraon7629,
author={Punit Saraon, Jamie Snider, Yannis Kalaidzidis, Leanne E Wybenga-Groot, Konstantin Weiss, Ankit Rai, Nikolina Radulovich, Luka Drecun, Nika Vučković, Adriana Vučetić, Victoria Wong, Brigitte Thériault, Nhu-An Pham, Jin H Park, Alessandro Datti, Jenny Wang, Shivanthy Pathmanathan, Farzaneh Aboualizadeh, Anna Lyakisheva, Zhong Yao, Yuhui Wang, Babu Joseph, Ahmed Aman, Michael F Moran, Michael Prakesch, Gennady Poda, Richard Marcellus, David Uehling, Miroslav Samaržija, Marko Jakopović, Ming-Sound Tsao, Frances A Shepherd, Adrian Sacher, Natasha Leighl, Anna Akhmanova, Rima Al-Awar, Marino Zerial, Igor Stagljar},
title={A drug discovery platform to identify compounds that inhibit EGFR triple mutants.},
journal ={Nature chemical biology},
volume={16},
issue ={5},
pages={577--586},
year=2020
}

Katarina Liedtke, Christina Alter, Anne Günther, Nadine Hövelmeyer, Robert Klopfleisch, Ronald Naumann, F Thomas Wunderlich, Jan Buer, Astrid M Westendorf, Wiebke Hansen
Endogenous CD83 Expression in CD4+ Conventional T Cells Controls Inflammatory Immune Responses.
J Immunol, Art. No. doi: 10.4049/jimmunol.2000042 (2020)
PubMed Source   

The glycoprotein CD83 is known to be expressed by different immune cells including activated CD4+Foxp3+ regulatory T cells (Tregs) and CD4+Foxp3- conventional T cells. However, the physiological function of endogenous CD83 in CD4+ T cell subsets is still unclear. In this study, we have generated a new CD83flox mouse line on BALB/c background, allowing for specific ablation of CD83 in T cells upon breeding with CD4-cre mice. Tregs from CD83flox/flox/CD4-cretg/wt mice had similar suppressive activity as Tregs from CD83flox/flox/CD4-crewt/wt wild-type littermates, suggesting that endogenous CD83 expression is dispensable for the inhibitory capacity of Tregs. However, CD83-deficient CD4+ conventional T cells showed elevated proliferation and IFN-γ secretion as well as an enhanced capacity to differentiate into Th1 cells and Th17 cells upon stimulation in vitro. T cell-specific ablation of CD83 expression resulted in aggravated contact hypersensitivity reaction accompanied by enhanced CD4+ T cell activation. Moreover, adoptive transfer of CD4+CD45RBhigh T cells from CD83flox/flox/CD4-cretg/wt mice into Rag2-deficient mice elicited more severe colitis associated with increased serum concentrations of IL-12 and elevated CD40 expression on CD11c+ dendritic cells (DCs). Strikingly, DCs from BALB/c mice cocultured with CD83-deficient CD4+ conventional T cells showed enhanced CD40 expression and IL-12 secretion compared with DCs cocultured with CD4+ conventional T cells from CD83flox/flox/CD4-crewt/wt wild-type mice. In summary, these results indicate that endogenous CD83 expression in CD4+ conventional T cells plays a crucial role in controlling CD4+ T cell responses, at least in part, by regulating the activity of CD11c+ DCs.
@article{Liedtke7659,
author={Katarina Liedtke, Christina Alter, Anne Günther, Nadine Hövelmeyer, Robert Klopfleisch, Ronald Naumann, F Thomas Wunderlich, Jan Buer, Astrid M Westendorf, Wiebke Hansen},
title={Endogenous CD83 Expression in CD4+ Conventional T Cells Controls Inflammatory Immune Responses.},
journal ={Journal of immunology (Baltimore, Md. : 1950)},
volume={},
pages={1--1},
year=2020
}

Alexandra Lewis, Ahmet C Berkyurek, Andre Greiner, Ahilya N Sawh, Ajay A Vashisht, Stephanie Merrett, Mathieu N Flamand, James Wohlschlegel, Mihail Sarov, Eric A Miska, Thomas F Duchaine
A Family of Argonaute-Interacting Proteins Gates Nuclear RNAi.
Mol Cell, Art. No. doi: 10.1016/j.molcel.2020.04.007 (2020)
PubMed Source   

Nuclear RNA interference (RNAi) pathways work together with histone modifications to regulate gene expression and enact an adaptive response to transposable RNA elements. In the germline, nuclear RNAi can lead to trans-generational epigenetic inheritance (TEI) of gene silencing. We identified and characterized a family of nuclear Argonaute-interacting proteins (ENRIs) that control the strength and target specificity of nuclear RNAi in C. elegans, ensuring faithful inheritance of epigenetic memories. ENRI-1/2 prevent misloading of the nuclear Argonaute NRDE-3 with small RNAs that normally effect maternal piRNAs, which prevents precocious nuclear translocation of NRDE-3 in the early embryo. Additionally, they are negative regulators of nuclear RNAi triggered from exogenous sources. Loss of ENRI-3, an unstable protein expressed mostly in the male germline, misdirects the RNAi response to transposable elements and impairs TEI. The ENRIs determine the potency and specificity of nuclear RNAi responses by gating small RNAs into specific nuclear Argonautes.
@article{Lewis7663,
author={Alexandra Lewis, Ahmet C Berkyurek, Andre Greiner, Ahilya N Sawh, Ajay A Vashisht, Stephanie Merrett, Mathieu N Flamand, James Wohlschlegel, Mihail Sarov, Eric A Miska, Thomas F Duchaine},
title={A Family of Argonaute-Interacting Proteins Gates Nuclear RNAi.},
journal ={Molecular cell},
volume={},
pages={1--1},
year=2020
}

Anke Weitzmann, Ronald Naumann, Anne Dudeck, Thomas Zerjatke, Alexander Gerbaulet, Axel Roers
Mast Cells Occupy Stable Clonal Territories in Adult Steady-State Skin.
J. Invest. Dermatol., Art. No. doi: 10.1016/j.jid.2020.03.963 (2020)
PubMed Source   

Mast cells (MCs) are tissue-resident hematopoietic cells intensely studied for their role as effectors in allergic immune responses. Yolk sac-derived embryonic MCs first populate tissues and are later replaced by definitive MCs. We show that definitive MC progenitors expand locally in skin and form clonal colonies that cover stable territories. In MC-deficient skin, colonies grow by proliferation of MCs at the border of the clonal territory. Clonal growth ceases at common borders of neighboring colonies. In steady-state, colony self-renewal is independent of bone marrow contribution and the clonal architecture remains fixed, if not disturbed by skin inflammation. Inflammatory cues increase MC density setpoint, stimulating influx of new progenitors from the bone marrow as well as proliferation of skin-resident cells. The expanding new arrivals disrespect territories of pre-existing MC clones. We conclude that during a limited window early in development, definitive MC precursors efficiently enter the skin, expand and self-maintain, occupying stable territories. In adulthood, circulating progenitors, excluded from steady-state skin, are recruited only into inflamed skin where they clonally expand alongside proliferating skin-resident MCs, disorganizing the original architecture of clonal territories.
@article{Weitzmann7652,
author={Anke Weitzmann, Ronald Naumann, Anne Dudeck, Thomas Zerjatke, Alexander Gerbaulet, Axel Roers},
title={Mast Cells Occupy Stable Clonal Territories in Adult Steady-State Skin.},
journal ={The Journal of investigative dermatology},
volume={},
pages={1--1},
year=2020
}

Jordina Guillén-Boixet, Andrii Kopach, Alex S Holehouse, Sina Wittmann, Marcus Jahnel, Raimund Schlüßler, Kyoohyun Kim, Irmela Trussina, Jie Wang, Daniel Mateju, Ina Poser, Shovamayee Maharana, Martine Ruer-Gruß, Doris Richter, Xiaojie Zhang, Young-Tae Chang, Jochen Guck, Alf Honigmann, Julia Mahamid, Anthony Hyman, Rohit V Pappu, Simon Alberti, Titus Franzmann
RNA-Induced Conformational Switching and Clustering of G3BP Drive Stress Granule Assembly by Condensation.
Cell, 181(2) 346-361 (2020)
PubMed Source   

Stressed cells shut down translation, release mRNA molecules from polysomes, and form stress granules (SGs) via a network of interactions that involve G3BP. Here we focus on the mechanistic underpinnings of SG assembly. We show that, under non-stress conditions, G3BP adopts a compact auto-inhibited state stabilized by electrostatic intramolecular interactions between the intrinsically disordered acidic tracts and the positively charged arginine-rich region. Upon release from polysomes, unfolded mRNAs outcompete G3BP auto-inhibitory interactions, engendering a conformational transition that facilitates clustering of G3BP through protein-RNA interactions. Subsequent physical crosslinking of G3BP clusters drives RNA molecules into networked RNA/protein condensates. We show that G3BP condensates impede RNA entanglement and recruit additional client proteins that promote SG maturation or induce a liquid-to-solid transition that may underlie disease. We propose that condensation coupled to conformational rearrangements and heterotypic multivalent interactions may be a general principle underlying RNP granule assembly.
@article{Guillén-Boixet7653,
author={Jordina Guillén-Boixet, Andrii Kopach, Alex S Holehouse, Sina Wittmann, Marcus Jahnel, Raimund Schlüßler, Kyoohyun Kim, Irmela Trussina, Jie Wang, Daniel Mateju, Ina Poser, Shovamayee Maharana, Martine Ruer-Gruß, Doris Richter, Xiaojie Zhang, Young-Tae Chang, Jochen Guck, Alf Honigmann, Julia Mahamid, Anthony Hyman, Rohit V Pappu, Simon Alberti, Titus Franzmann},
title={RNA-Induced Conformational Switching and Clustering of G3BP Drive Stress Granule Assembly by Condensation.},
journal ={Cell},
volume={181},
issue ={2},
pages={346--361},
year=2020
}

Kristina Kleinschnitz, Nina Vießmann, Mareike A Jordan, Stefan K Heidmann
Condensin I is required for faithful meiosis in Drosophila males.
Chromosoma, Art. No. doi: 10.1007/s00412-020-00733-w (2020)
PubMed Source   

The heteropentameric condensin complexes play vital roles in the formation and faithful segregation of mitotic chromosomes in eukaryotes. While the different contributions of the two common condensin complexes, condensin I and condensin II, to chromosome morphology and behavior in mitosis have been thoroughly investigated, much less is known about the specific roles of the two complexes during meiotic divisions. In Drosophila melanogaster, faithful mitotic divisions depend on functional condensin I, but not on condensin II. However, meiotic divisions in Drosophila males require functional condensin II subunits. The role of condensin I during male meiosis in Drosophila has been unresolved. Here, we show that condensin I-specific subunits localize to meiotic chromatin in both meiosis I and II during Drosophila spermatogenesis. Live cell imaging reveals defects during meiotic divisions after RNAi-mediated knockdown of condensin I-specific mRNAs. This phenotype correlates with reduced male fertility and an increase in nondisjunction events both in meiosis I and meiosis II. Consistently, a reduction in male fertility was also observed after proteasome-mediated degradation of the condensin I subunit Barren. Taken together, our results demonstrate an essential role of condensin I during male meiosis in Drosophila melanogaster.
@article{Kleinschnitz7665,
author={Kristina Kleinschnitz, Nina Vießmann, Mareike A Jordan, Stefan K Heidmann},
title={Condensin I is required for faithful meiosis in Drosophila males.},
journal ={Chromosoma},
volume={},
pages={1--1},
year=2020
}