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Matthäus Mittasch, Vanna M. Tran, Manolo U. Rios, Anatol Fritsch, Stephen Enos, Beatriz Ferreira Gomes, Alec Bond, Moritz Kreysing, Jeffrey Woodruff
Regulated changes in material properties underlie centrosome disassembly during mitotic exit.
J Cell Biol, 219(4) Art. No. doi: 10.1083/jcb.201912036 (2020)
PubMed Source   

Centrosomes must resist microtubule-mediated forces for mitotic chromosome segregation. During mitotic exit, however, centrosomes are deformed and fractured by those same forces, which is a key step in centrosome disassembly. How the functional material properties of centrosomes change throughout the cell cycle, and how they are molecularly tuned, remain unknown. Here, we used optically induced flow perturbations to determine the molecular basis of centrosome strength and ductility in C. elegans embryos. We found that both properties declined sharply at anaphase onset, long before natural disassembly. This mechanical transition required PP2A phosphatase and correlated with inactivation of PLK-1 (Polo kinase) and SPD-2 (Cep192). In vitro, PLK-1 and SPD-2 directly protected centrosome scaffolds from force-induced disassembly. Our results suggest that, before anaphase, PLK-1 and SPD-2 respectively confer strength and ductility to the centrosome scaffold so that it can resist microtubule-pulling forces. In anaphase, centrosomes lose PLK-1 and SPD-2 and transition to a weak, brittle state that enables force-mediated centrosome disassembly.
@article{Mittasch7611,
author={Matthäus Mittasch, Vanna M. Tran, Manolo U. Rios, Anatol Fritsch, Stephen Enos, Beatriz Ferreira Gomes, Alec Bond, Moritz Kreysing, Jeffrey Woodruff},
title={Regulated changes in material properties underlie centrosome disassembly during mitotic exit.},
journal ={The Journal of cell biology},
volume={219},
issue ={4},
pages={1--1},
year=2020
}

Takashi Namba, Judit Dóczi, Anneline Pinson, Lei Xing, Nereo Kalebic, Michaela Wilsch-Bräuninger, Katherine S. Long, Samir Vaid, Janelle Lauer, Aliona Bogdanova, Barbara Borgonovo, Anna Shevchenko, Patrick Keller, David N. Drechsel, Teymuras V. Kurzchalia, Pauline Wimberger, Christos Chinopoulos, Wieland Huttner
Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neocortical Progenitors by Glutaminolysis.
Neuron, 105(5) 867-881 (2020)
PubMed Source   

The human-specific gene ARHGAP11B is preferentially expressed in neural progenitors of fetal human neocortex and increases abundance and proliferation of basal progenitors (BPs), which have a key role in neocortex expansion. ARHGAP11B has therefore been implicated in the evolutionary expansion of the human neocortex, but its mode of action has been unknown. Here, we show that ARHGAP11B is imported into mitochondria, where it interacts with the adenine nucleotide translocase (ANT) and inhibits the mitochondrial permeability transition pore (mPTP). BP expansion by ARHGAP11B requires its presence in mitochondria, and pharmacological inhibition of ANT function or mPTP opening mimic BP expansion by ARHGAP11B. Searching for the underlying metabolic basis, we find that BP expansion by ARHGAP11B requires glutaminolysis, the conversion of glutamine to glutamate for the tricarboxylic acid (TCA) cycle. Hence, an ARHGAP11B-induced, mitochondria-based effect on BP metabolism that is a hallmark of highly mitotically active cells appears to underlie its role in neocortex expansion.
@article{Namba7585,
author={Takashi Namba, Judit Dóczi, Anneline Pinson, Lei Xing, Nereo Kalebic, Michaela Wilsch-Bräuninger, Katherine S. Long, Samir Vaid, Janelle Lauer, Aliona Bogdanova, Barbara Borgonovo, Anna Shevchenko, Patrick Keller, David N. Drechsel, Teymuras V. Kurzchalia, Pauline Wimberger, Christos Chinopoulos, Wieland Huttner},
title={Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neocortical Progenitors by Glutaminolysis.},
journal ={Neuron},
volume={105},
issue ={5},
pages={867--881},
year=2020
}

Nikitas Georgakopoulos, Nicole Prior, Brigitte Angres, Gianmarco Mastrogiovanni, Alex Cagan, Daisy Harrison, Christopher J Hindley, Robert Arnes-Benito, Siong-Seng Liau, Abbie Curd, Natasha Ivory, Benjamin D Simons, Inigo Martincorena, Helmut Wurst, Kourosh Saeb-Parsy, Meritxell Huch
Long-term expansion, genomic stability and in vivo safety of adult human pancreas organoids.
BMC Dev Biol, 20(1) Art. No. 4 (2020)
PubMed Source   

Pancreatic organoid systems have recently been described for the in vitro culture of pancreatic ductal cells from mouse and human. Mouse pancreatic organoids exhibit unlimited expansion potential, while previously reported human pancreas organoid (hPO) cultures do not expand efficiently long-term in a chemically defined, serum-free medium. We sought to generate a 3D culture system for long-term expansion of human pancreas ductal cells as hPOs to serve as the basis for studies of human pancreas ductal epithelium, exocrine pancreatic diseases and the development of a genomically stable replacement cell therapy for diabetes mellitus.
@article{Georgakopoulos7628,
author={Nikitas Georgakopoulos, Nicole Prior, Brigitte Angres, Gianmarco Mastrogiovanni, Alex Cagan, Daisy Harrison, Christopher J Hindley, Robert Arnes-Benito, Siong-Seng Liau, Abbie Curd, Natasha Ivory, Benjamin D Simons, Inigo Martincorena, Helmut Wurst, Kourosh Saeb-Parsy, Meritxell Huch},
title={Long-term expansion, genomic stability and in vivo safety of adult human pancreas organoids.},
journal ={BMC developmental biology},
volume={20},
issue ={1},
pages={null--null},
year=2020
}

Ritika Giri, Dimitrios Papadopoulos, Diana M Posadas, Hemanth K Potluri, Pavel Tomancak, Madhav Mani, Richard W Carthew
Ordered patterning of the sensory system is susceptible to stochastic features of gene expression.
Elife, 9 Art. No. e53638 (2020)
PubMed Source   

Sensory neuron numbers and positions are precisely organized to accurately map environmental signals in the brain. This precision emerges from biochemical processes within and between cells that are inherently stochastic. We investigated impact of stochastic gene expression on pattern formation, focusing on senseless (sens), a key determinant of sensory fate in Drosophila. Perturbing microRNA regulation or genomic location of sens produced distinct noise signatures. Noise was greatly enhanced when both sens alleles were present in homologous loci such that each allele was regulated in trans by the other allele. This led to disordered patterning. In contrast, loss of microRNA repression of sens increased protein abundance but not sensory pattern disorder. This suggests that gene expression stochasticity is a critical feature that must be constrained during development to allow rapid yet accurate cell fate resolution.
@article{Giri7631,
author={Ritika Giri, Dimitrios Papadopoulos, Diana M Posadas, Hemanth K Potluri, Pavel Tomancak, Madhav Mani, Richard W Carthew},
title={Ordered patterning of the sensory system is susceptible to stochastic features of gene expression.},
journal ={eLife},
volume={9},
pages={null--null},
year=2020
}

Sören Reinke, Mary Linge, Hans H Diebner, H Luksch, Silke Glage, Anne Gocht, Avril A B Robertson, Matthew A Cooper, Sigrun R Hofmann, Ronald Naumann, Mihail Sarov, Rayk Behrendt, Axel Roers, Frank Pessler, Joachim Roesler, Angela Rösen-Wolff, Stefan Winkler
Non-canonical Caspase-1 Signaling Drives RIP2-Dependent and TNF-α-Mediated Inflammation In Vivo.
Cell Rep, 30(8) 2501-2511 (2020)
PubMed Source   

Pro-inflammatory caspase-1 is a key player in innate immunity. Caspase-1 processes interleukin (IL)-1β and IL-18 to their mature forms and triggers pyroptosis. These caspase-1 functions are linked to its enzymatic activity. However, loss-of-function missense mutations in CASP1 do not prevent autoinflammation in patients, despite decreased IL-1β production. In vitro data suggest that enzymatically inactive caspase-1 drives inflammation via enhanced nuclear factor κB (NF-κB) activation, independent of IL-1β processing. Here, we report two mouse models of enzymatically inactive caspase-1-C284A, demonstrating the relevance of this pathway in vivo. In contrast to Casp1-/- mice, caspase-1-C284A mice show pronounced hypothermia and increased levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and IL-6 when challenged with lipopolysaccharide (LPS). Caspase-1-C284A signaling is RIP2 dependent and mediated by TNF-α but independent of the NLRP3 inflammasome. LPS-stimulated whole blood from patients carrying loss-of-function missense mutations in CASP1 secretes higher amounts of TNF-α. Taken together, these results reveal non-canonical caspase-1 signaling in vivo.
@article{Reinke7619,
author={Sören Reinke, Mary Linge, Hans H Diebner, H Luksch, Silke Glage, Anne Gocht, Avril A B Robertson, Matthew A Cooper, Sigrun R Hofmann, Ronald Naumann, Mihail Sarov, Rayk Behrendt, Axel Roers, Frank Pessler, Joachim Roesler, Angela Rösen-Wolff, Stefan Winkler},
title={Non-canonical Caspase-1 Signaling Drives RIP2-Dependent and TNF-α-Mediated Inflammation In Vivo.},
journal ={Cell reports},
volume={30},
issue ={8},
pages={2501--2511},
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, Art. No. doi: 10.1038/s41589-020-0484-2 (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={},
pages={1--1},
year=2020
}

Lillian Garrett, Yoon Jeung Chang, Kristina M Niedermeier, Tamara Heermann, Wolfgang Enard, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabe de Angelis, Wieland Huttner, Wolfgang Wurst, Sabine M Hölter
A truncating Aspm allele leads to a complex cognitive phenotype and region-specific reductions in parvalbuminergic neurons.
Transl Psychiatry, 10(1) 66-66 (2020)
PubMed Source   

Neurodevelopmental disorders are heterogeneous and identifying shared genetic aetiologies and converging signalling pathways affected could improve disease diagnosis and treatment. Truncating mutations of the abnormal spindle-like microcephaly associated (ASPM) gene cause autosomal recessive primary microcephaly (MCPH) in humans. ASPM is a positive regulator of Wnt/β-Catenin signalling and controls symmetric to asymmetric cell division. This process balances neural progenitor proliferation with differentiation during embryogenesis, the malfunction of which could interfere with normal brain development. ASPM mutations may play a role also in other neurodevelopmental disorders, nevertheless, we lack the details of how or to what extent. We therefore assessed neurodevelopmental disease and circuit endophenotypes in mice with a truncating Aspm1-7 mutation. Aspm1-7 mice exhibited impaired short- and long-term object recognition memory and markedly enhanced place learning in the IntelliCage®. This behaviour pattern is reminiscent of a cognitive phenotype seen in mouse models and patients with a rare form of autism spectrum disorder (ASD) as well as in mouse models of altered Wnt signalling. These alterations were accompanied by ventriculomegaly, corpus callosum dysgenesis and decreased parvalbumin (PV)+ interneuron numbers in the hippocampal Cornu Ammonis (CA) region and thalamic reticular nucleus (TRN). PV+ cell number correlated to object recognition (CA and TRN) and place learning (TRN). This opens the possibility that, as well as causing MCPH, mutant ASPM potentially contributes to other neurodevelopmental disorders such as ASD through altered parvalbuminergic interneuron development affecting cognitive behaviour. These findings provide important information for understanding the genetic overlap and improved treatment of neurodevelopmental disorders associated with ASPM.
@article{Garrett7627,
author={Lillian Garrett, Yoon Jeung Chang, Kristina M Niedermeier, Tamara Heermann, Wolfgang Enard, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabe de Angelis, Wieland Huttner, Wolfgang Wurst, Sabine M Hölter},
title={A truncating Aspm allele leads to a complex cognitive phenotype and region-specific reductions in parvalbuminergic neurons.},
journal ={Translational psychiatry},
volume={10},
issue ={1},
pages={66--66},
year=2020
}

Jussi Helppi, Ronald Naumann, Oliver Zierau
Phytoestrogen-containing diets offer benefits for mouse embryology but lead to fewer offspring being produced.
Lab Anim, Art. No. doi: doi: 10.1177/0023677219898486 (2020)
PubMed Source   

One of the most commonly used protein sources in rodent diets is soy, which is naturally rich in phytoestrogens. Although phytoestrogens have shown potential health benefits in humans, they may also have the ability to disrupt reproduction. Consequently, there has been a tendency to try to exclude them from rodent diets. In the current study, we investigated whether phytoestrogen content in the mouse diet could affect reproduction in mice used as embryo donors. Donor mice (C57BL/6JOlaHsd) were maintained with three different diets: high phytoestrogen (ca. 400 mg/kg genistein), low phytoestrogen (ca. 10 mg/kg genistein) and standard breeding diet (ca. 120 mg/kg genistein). Mice fed a high phytoestrogen diet had a high yield of plugs, embryos, and injectable embryos, as well as producing good quality embryos. Results from donor mice fed a low phytoestrogen diet were consistently but only slightly inferior, whereas mice fed a standard diet performed the poorest. Interestingly, the largest number of born and weaned offspring were observed when recipient females received embryos from the standard diet group. Sperm yield and quality of stud males did not differ between the groups. We surmize that for experimental endpoints requiring fertilized embryos it may be more beneficial to feed mice a diet containing phytoestrogen, but if the goal is to produce transgenic mice, a diet high in phytoestrogen may be inadvisable. In conclusion, care should be taken when selecting a diet for experimental mouse colonies as phytoestrogen could influence the study outcome.
@article{Helppi7613,
author={Jussi Helppi, Ronald Naumann, Oliver Zierau},
title={Phytoestrogen-containing diets offer benefits for mouse embryology but lead to fewer offspring being produced.},
journal ={Laboratory animals},
volume={},
pages={1--1},
year=2020
}

Sona Valuchova, Pavlina Mikulkova, Jana Pecinkova, Jana Klimova, Michal Krumnikl, Petr Bainar, Stefan Heckmann, Pavel Tomancak, Karel Riha
Imaging plant germline differentiation within Arabidopsis flowers by light sheet microscopy.
Elife, 9 Art. No. e52546 (2020)
PubMed Source   

In higher plants, germline differentiation occurs during a relatively short period within developing flowers. Understanding of the mechanisms that govern germline differentiation lags behind other plant developmental processes. This is largely because the germline is restricted to relatively few cells buried deep within floral tissues, which makes them difficult to study. To overcome this limitation, we have developed a methodology for live imaging of the germ cell lineage within floral organs of Arabidopsis using light sheet fluorescence microscopy. We have established reporter lines, cultivation conditions, and imaging protocols for high-resolution microscopy of developing flowers continuously for up to several days. We used multiview imagining to reconstruct a three-dimensional model of a flower at subcellular resolution. We demonstrate the power of this approach by capturing male and female meiosis, asymmetric pollen division, movement of meiotic chromosomes, and unusual restitution mitosis in tapetum cells. This method will enable new avenues of research into plant sexual reproduction.
@article{Valuchova7610,
author={Sona Valuchova, Pavlina Mikulkova, Jana Pecinkova, Jana Klimova, Michal Krumnikl, Petr Bainar, Stefan Heckmann, Pavel Tomancak, Karel Riha},
title={Imaging plant germline differentiation within Arabidopsis flowers by light sheet microscopy.},
journal ={eLife},
volume={9},
pages={null--null},
year=2020
}

Masin Abo-Rady, Norman Kalmbach, Arun Pal, Carina Schludi, Antje Janosch, Tanja Richter, Petra Freitag, Marc Bickle, Anne-Karin Kahlert, Susanne Petri, Stefan Stefanov, Hannes Glass, Selma Staege, Walter Just, Rajat Bhatnagar, Dieter Edbauer, Andreas Hermann, Florian Wegner, Jared Sterneckert
Knocking out C9ORF72 Exacerbates Axonal Trafficking Defects Associated with Hexanucleotide Repeat Expansion and Reduces Levels of Heat Shock Proteins.
Stem Cell Reports, Art. No. doi: 10.1016/j.stemcr.2020.01.010 (2020)
PubMed Source   

In amyotrophic lateral sclerosis (ALS) motor neurons (MNs) undergo dying-back, where the distal axon degenerates before the soma. The hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of ALS, but the mechanism of pathogenesis is largely unknown with both gain- and loss-of-function mechanisms being proposed. To better understand C9ORF72-ALS pathogenesis, we generated isogenic induced pluripotent stem cells. MNs with HRE in C9ORF72 showed decreased axonal trafficking compared with gene corrected MNs. However, knocking out C9ORF72 did not recapitulate these changes in MNs from healthy controls, suggesting a gain-of-function mechanism. In contrast, knocking out C9ORF72 in MNs with HRE exacerbated axonal trafficking defects and increased apoptosis as well as decreased levels of HSP70 and HSP40, and inhibition of HSPs exacerbated ALS phenotypes in MNs with HRE. Therefore, we propose that the HRE in C9ORF72 induces ALS pathogenesis via a combination of gain- and loss-of-function mechanisms.
@article{Abo-Rady7632,
author={Masin Abo-Rady, Norman Kalmbach, Arun Pal, Carina Schludi, Antje Janosch, Tanja Richter, Petra Freitag, Marc Bickle, Anne-Karin Kahlert, Susanne Petri, Stefan Stefanov, Hannes Glass, Selma Staege, Walter Just, Rajat Bhatnagar, Dieter Edbauer, Andreas Hermann, Florian Wegner, Jared Sterneckert},
title={Knocking out C9ORF72 Exacerbates Axonal Trafficking Defects Associated with Hexanucleotide Repeat Expansion and Reduces Levels of Heat Shock Proteins.},
journal ={Stem cell reports},
volume={},
pages={1--1},
year=2020
}