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Donato Santovito, Virginia Egea, Kiril Bidzhekov, Lucia Natarelli, André Mourão, Xavier Blanchet, Kanin Wichapong, Maria Aslani, Coy Brunßen, Michael Horckmans, Michael Hristov, Arie Geerlof, Esther Lutgens, Mat J A P Daemen, Tilman M Hackeng, Christian Ries, Trian Chavakis, Henning Morawietz, Ronald Naumann, Philipp von Hundelshausen, Sabine Steffens, Johan Duchêne, Remco T A Megens, Michael Sattler, Christian Weber
Autophagy unleashes noncanonical microRNA functions.
Autophagy, 1-3 (2020)
PubMed Source   

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression which act by guiding AGO (argonaute) proteins to target RNA transcripts in the RNA-induced silencing complex (RISC). This macromolecular complex includes multiple additional components (e.g., TNRC6A) that allow for interaction with enzymes mediating inhibition of translation or RNA decay. However, miRNAs also reside in low-molecular weight complexes without being engaged in target repression, and their function in this context is largely unknown. Our recent findings show that endothelial cells exposed to protective high-shear stress or MTORC inhibition activate the macroautophagy/autophagy machinery to sustain viability by promoting differential trafficking of MIR126 strands and by enabling unconventional features of MIR126-5p. Whereas MIR126-3p is degraded upon autophagy activation, MIR126-5p interacts with the RNA-binding protein MEX3A to form a ternary complex with AGO2. This complex forms on the autophagosomal surface and facilitates its nuclear localization. Once in the nucleus, MIR126-5p dissociates from AGO2 and establishes aptamer-like interactions with the effector CASP3 (caspase 3). The binding to MIR126-5p prevents dimerization and proper active site formation of CASP3, thus inhibiting proteolytic activity and limiting apoptosis. Disrupting this pathway in vivo by genetic deletion of Mex3a or by specific deficiency of endothelial autophagy aggravates endothelial apoptosis and exacerbates the progression of atherosclerosis. The direct inhibition of CASP3 by MIR126-5p reveals a non-canonical mechanism by which miRNAs can modulate protein function and mediate the autophagy-apoptosis crosstalk.
@article{Santovito7816,
author={Donato Santovito, Virginia Egea, Kiril Bidzhekov, Lucia Natarelli, André Mourão, Xavier Blanchet, Kanin Wichapong, Maria Aslani, Coy Brunßen, Michael Horckmans, Michael Hristov, Arie Geerlof, Esther Lutgens, Mat J A P Daemen, Tilman M Hackeng, Christian Ries, Trian Chavakis, Henning Morawietz, Ronald Naumann, Philipp von Hundelshausen, Sabine Steffens, Johan Duchêne, Remco T A Megens, Michael Sattler, Christian Weber},
title={Autophagy unleashes noncanonical microRNA functions.},
journal ={Autophagy},
volume={},
pages={1--3},
year=2020
}

Stephanie Spannl, Tomasz Buhl, Ioannis Nellas, Salma A Zeidan, K Venkatesan Iyer, Helena Khaliullina, Carsten Schultz, André Nadler, Natalie Dye, Suzanne Eaton
Glycolysis regulates Hedgehog signalling via the plasma membrane potential.
EMBO J, Art. No. e101767 (2020)
PubMed Source   

Changes in cell metabolism and plasma membrane potential have been linked to shifts between tissue growth and differentiation, and to developmental patterning. How such changes mediate these effects is poorly understood. Here, we use the developing wing of Drosophila to investigate the interplay between cell metabolism and a key developmental regulator-the Hedgehog (Hh) signalling pathway. We show that reducing glycolysis both lowers steady-state levels of ATP and stabilizes Smoothened (Smo), the 7-pass transmembrane protein that transduces the Hh signal. As a result, the transcription factor Cubitus interruptus accumulates in its full-length, transcription activating form. We show that glycolysis is required to maintain the plasma membrane potential and that plasma membrane depolarization blocks cellular uptake of N-acylethanolamides-lipoprotein-borne Hh pathway inhibitors required for Smo destabilization. Similarly, pharmacological inhibition of glycolysis in mammalian cells induces ciliary translocation of Smo-a key step in pathway activation-in the absence of Hh. Thus, changes in cell metabolism alter Hh signalling through their effects on plasma membrane potential.
@article{Spannl7815,
author={Stephanie Spannl, Tomasz Buhl, Ioannis Nellas, Salma A Zeidan, K Venkatesan Iyer, Helena Khaliullina, Carsten Schultz, André Nadler, Natalie Dye, Suzanne Eaton},
title={Glycolysis regulates Hedgehog signalling via the plasma membrane potential.},
journal ={The EMBO journal},
volume={},
pages={null--null},
year=2020
}

Nicolette G Moreau, Nicolas Martin, Pierangelo Gobbo, T-Y Dora Tang, Stephen Mann
Spontaneous membrane-less multi-compartmentalization via aqueous two-phase separation in complex coacervate micro-droplets.
Chem Commun (Camb), Art. No. doi: 10.1039/d0cc05399f (2020)
PubMed Source   

Polyelectrolyte/nucleotide multiphase complex coacervate droplets are produced by internalized aqueous two-phase separation and used for the spatially dependent chemical transfer of sugar molecules, providing a step towards the development of membrane-free "organelles" within coacervate-based protocells.
@article{Moreau7812,
author={Nicolette G Moreau, Nicolas Martin, Pierangelo Gobbo, T-Y Dora Tang, Stephen Mann},
title={Spontaneous membrane-less multi-compartmentalization via aqueous two-phase separation in complex coacervate micro-droplets.},
journal ={Chemical communications (Cambridge, England)},
volume={},
pages={1--1},
year=2020
}

Damla Kaptan, Sider Penkov, Xingyu Zhang, Vamshidhar Gade, Bharath Kumar Raghuraman, Roberta Galli, Júlio L Sampaio, Robert Haase, Edmund Koch, Andrej Shevchenko, Vasily Zaburdaev, Teymuras V. Kurzchalia
Exogenous ethanol induces a metabolic switch that prolongs the survival of Caenorhabditis elegans dauer larva and enhances its resistance to desiccation.
Aging Cell, 13214-13214 (2020)
PubMed Source   

The dauer larva of Caenorhabditis elegans, destined to survive long periods of food scarcity and harsh environment, does not feed and has a very limited exchange of matter with the exterior. It was assumed that the survival time is determined by internal energy stores. Here, we show that ethanol can provide a potentially unlimited energy source for dauers by inducing a controlled metabolic shift that allows it to be metabolized into carbohydrates, amino acids, and lipids. Dauer larvae provided with ethanol survive much longer and have greater desiccation tolerance. On the cellular level, ethanol prevents the deterioration of mitochondria caused by energy depletion. By modeling the metabolism of dauers of wild-type and mutant strains with and without ethanol, we suggest that the mitochondrial health and survival of an organism provided with an unlimited source of carbon depends on the balance between energy production and toxic product(s) of lipid metabolism.
@article{Kaptan7813,
author={Damla Kaptan, Sider Penkov, Xingyu Zhang, Vamshidhar Gade, Bharath Kumar Raghuraman, Roberta Galli, Júlio L Sampaio, Robert Haase, Edmund Koch, Andrej Shevchenko, Vasily Zaburdaev, Teymuras V. Kurzchalia},
title={Exogenous ethanol induces a metabolic switch that prolongs the survival of Caenorhabditis elegans dauer larva and enhances its resistance to desiccation.},
journal ={Aging cell},
volume={},
pages={13214--13214},
year=2020
}

Ilia Zhernov, Stefan Diez, Marcus Braun, Zdenek Lansky
Intrinsically Disordered Domain of Kinesin-3 Kif14 Enables Unique Functional Diversity.
Curr Biol, Art. No. doi: 10.1016/j.cub.2020.06.039 (2020)
PubMed Source   

In addition to their force-generating motor domains, kinesin motor proteins feature various accessory domains enabling them to fulfill a variety of functions in the cell. Human kinesin-3, Kif14, localizes to the midbody of the mitotic spindle and is involved in the progression of cytokinesis. The specific motor properties enabling Kif14's cellular functions, however, remain unknown. Here, we show in vitro that the intrinsically disordered N-terminal domain of Kif14 enables unique functional diversity of the kinesin. Using single molecule TIRF microscopy, we found that Kif14 exists either as a diffusible monomer or as processive dimer and that the disordered domain (1) enables diffusibility of the monomeric Kif14, (2) renders the dimeric Kif14 super-processive and enables the kinesin to pass through highly crowded areas, (3) enables robust, autonomous Kif14 tracking of growing microtubule tips, independent of microtubule end-binding (EB) proteins, and (4) is sufficient to enable crosslinking of parallel microtubules and necessary to enable Kif14-driven sliding of antiparallel ones. We explain these features of Kif14 by the observed diffusible interaction of the disordered domain with the microtubule lattice and the observed increased affinity of the disordered domain for GTP-bound tubulin. We suggest that the disordered domain tethers the motor domain to the microtubule providing a diffusible foothold and a regulatory hub, tuning the kinesin's interaction with microtubules. Our findings thus exemplify pliable protein tethering as a fundamental mechanism of molecular motor regulation.
@article{Zhernov7712,
author={Ilia Zhernov, Stefan Diez, Marcus Braun, Zdenek Lansky},
title={Intrinsically Disordered Domain of Kinesin-3 Kif14 Enables Unique Functional Diversity.},
journal ={Current biology : CB},
volume={},
pages={1--1},
year=2020
}

Barbara Stepien, Ronald Naumann, Anja Holtz, Jussi Helppi, Wieland Huttner, Samir Vaid
Lengthening Neurogenic Period during Neocortical Development Causes a Hallmark of Neocortex Expansion.
Curr Biol, Art. No. doi: 10.1016/j.cub.2020.08.046 (2020)
PubMed Source   

A hallmark of the evolutionary expansion of the neocortex is a specific increase in the number of neurons generated for the upper neocortical layers during development. The cause underlying this increase is unknown. Here, we show that lengthening the neurogenic period during neocortical development is sufficient to specifically increase upper-layer neuron generation. Thus, embryos of mouse strains with longer gestation exhibited a longer neurogenic period and generated more upper-layer, but not more deep-layer, neurons than embryos with shorter gestation. Accordingly, long-gestation embryos showed a greater abundance of neurogenic progenitors in the subventricular zone than short-gestation embryos at late stages of cortical neurogenesis. Analysis of a mouse-rat chimeric embryo, developing inside a rat mother, pointed to factors in the rat environment that influenced the upper-layer neuron generation by the mouse progenitors. Exploring a potential maternal source of such factors, short-gestation strain mouse embryos transferred to long-gestation strain mothers exhibited an increase in the length of the neurogenic period and upper-layer neuron generation. The opposite was the case for long-gestation strain mouse embryos transferred to short-gestation strain mothers, indicating a dominant maternal influence on the length of the neurogenic period and hence upper-layer neuron generation. In summary, our study uncovers a hitherto unknown link between embryonic cortical neurogenesis and the maternal gestational environment and provides experimental evidence that lengthening the neurogenic period during neocortical development underlies a key aspect of neocortical expansion.
@article{Stepien7777,
author={Barbara Stepien, Ronald Naumann, Anja Holtz, Jussi Helppi, Wieland Huttner, Samir Vaid},
title={Lengthening Neurogenic Period during Neocortical Development Causes a Hallmark of Neocortex Expansion.},
journal ={Current biology : CB},
volume={},
pages={1--1},
year=2020
}

Juliana G. Roscito, Kaushikaram Subramanian, Ronald Naumann, Mihail Sarov, Anna Shevchenko, Aliona Bogdanova, Thomas Kurth, Leo Foerster, Moritz Kreysing, Michael Hiller
Recapitulating evolutionary divergence in a single cis-regulatory element is sufficient to cause expression changes of the lens gene Tdrd7.
Mol Biol Evol, Art. No. doi: 10.1093/molbev/msaa212 (2020)
PubMed Source   

Mutations in cis-regulatory elements play important roles for phenotypic changes during evolution. Eye degeneration in the blind mole rat (BMR; Nannospalax galili) and other subterranean mammals is significantly associated with widespread divergence of eye regulatory elements, but the effect of these regulatory mutations on eye development and function has not been explored. Here, we investigate the effect of mutations observed in the BMR sequence of a conserved non-coding element upstream of Tdrd7, a pleiotropic gene required for lens development and spermatogenesis. We first show that this conserved element is a transcriptional repressor in lens cells and that the BMR sequence partially lost repressor activity. Next, we recapitulated evolutionary changes in this element by precisely replacing the endogenous regulatory element in a mouse line by the orthologous BMR sequence with CRISPR-Cas9. Strikingly, this repressor replacement caused a more than two-fold up-regulation of Tdrd7 in the developing lens; however, increased mRNA level does not result in a corresponding increase in TDRD7 protein nor an obvious lens phenotype, possibly explained by buffering at the posttranscriptional level. Our results are consistent with eye degeneration in subterranean mammals having a polygenic basis where many small-effect mutations in different eye-regulatory elements collectively contribute to phenotypic differences.
@article{Roscito7696,
author={Juliana G. Roscito, Kaushikaram Subramanian, Ronald Naumann, Mihail Sarov, Anna Shevchenko, Aliona Bogdanova, Thomas Kurth, Leo Foerster, Moritz Kreysing, Michael Hiller},
title={Recapitulating evolutionary divergence in a single cis-regulatory element is sufficient to cause expression changes of the lens gene Tdrd7.},
journal ={Molecular biology and evolution},
volume={},
pages={1--1},
year=2020
}

Robert W Fernandez, Kimberly Wei, Erin Y Wang, Deimante Mikalauskaite, Andrew Olson, Judy Pepper, Nakeirah Christie, Seongseop Kim, Susanne Weissenborn, Mihail Sarov, Michael R Koelle
Cellular Expression and Functional Roles of All 26 Neurotransmitter GPCRs in the C. elegans Egg-Laying Circuit.
J Neurosci, Art. No. doi: 10.1523/JNEUROSCI.1357-20.2020 (2020)
PubMed Source   

Maps of the synapses made and neurotransmitters released by all neurons in model systems such as C. elegans have left still unresolved how neural circuits integrate and respond to neurotransmitter signals. Using the egg-laying circuit of C. elegans as a model, we mapped which cells express each of the 26 neurotransmitter G protein coupled receptors (GPCRs) of this organism and also genetically analyzed the functions of all 26 GPCRs. We found that individual neurons express many distinct receptors, epithelial cells often express neurotransmitter receptors, and receptors are often positioned to receive extrasynaptic signals. Receptor knockouts reveal few egg-laying defects under standard lab conditions, suggesting the receptors function redundantly or regulate egg-laying only in specific conditions; however, increasing receptor signaling through overexpression more efficiently reveals receptor functions. This map of neurotransmitter GPCR expression and function in the egg-laying circuit provides a model for understanding GPCR signaling in other neural circuits.SIGNIFICANCE STATEMENTNeurotransmitters signal through G protein coupled receptors (GPCRs) to modulate activity of neurons, and changes in such signaling can underlie conditions such as depression and Parkinson's disease. To determine how neurotransmitter GPCRs together help regulate function of a neural circuit, we analyzed the simple egg-laying circuit in the model organism C. elegans. We identified all the cells that express every neurotransmitter GPCR and genetically analyzed how each GPCR affects the behavior the circuit produces. We found that many neurotransmitter GPCRs are expressed in each neuron, that neurons also appear to use these receptors to communicate with other cell types, and that GPCRs appear to often act redundantly or only under specific conditions to regulate circuit function.
@article{Fernandez7750,
author={Robert W Fernandez, Kimberly Wei, Erin Y Wang, Deimante Mikalauskaite, Andrew Olson, Judy Pepper, Nakeirah Christie, Seongseop Kim, Susanne Weissenborn, Mihail Sarov, Michael R Koelle},
title={Cellular Expression and Functional Roles of All 26 Neurotransmitter GPCRs in the C. elegans Egg-Laying Circuit.},
journal ={The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume={},
pages={1--1},
year=2020
}

Joana Damas, Graham M Hughes, Kathleen C Keough, Corrie A Painter, Nicole S Persky, Marco Corbo, Michael Hiller, Klaus-Peter Koepfli, Andreas R Pfenning, Huabin Zhao, Diane P Genereux, Ross Swofford, Katherine S Pollard, Oliver A Ryder, Martin T Nweeia, Kerstin Lindblad-Toh, Emma Teeling, Elinor K Karlsson, Harris A Lewin
Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates.
Proc Natl Acad Sci U.S.A., Art. No. doi: 10.1073/pnas.2010146117 (2020)
PubMed Source   

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
@article{Damas7743,
author={Joana Damas, Graham M Hughes, Kathleen C Keough, Corrie A Painter, Nicole S Persky, Marco Corbo, Michael Hiller, Klaus-Peter Koepfli, Andreas R Pfenning, Huabin Zhao, Diane P Genereux, Ross Swofford, Katherine S Pollard, Oliver A Ryder, Martin T Nweeia, Kerstin Lindblad-Toh, Emma Teeling, Elinor K Karlsson, Harris A Lewin},
title={Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates.},
journal ={Proceedings of the National Academy of Sciences of the United States of America},
volume={},
pages={1--1},
year=2020
}

Nereo Kalebic, Wieland Huttner
Basal Progenitor Morphology and Neocortex Evolution.
Trends Neurosci., Art. No. doi: 10.1016/j.tins.2020.07.009 (2020)
PubMed Source   

The evolutionary expansion of the mammalian neocortex is widely considered to be a basis of increased cognitive abilities. This expansion is a consequence of the enhanced production of neurons during the fetal/embryonic development of the neocortex, which in turn reflects an increased proliferative capacity of neural progenitor cells; in particular basal progenitors (BPs). The remarkable heterogeneity of BP subtypes across mammals, notably their various morphotypes and molecular fingerprints, which has recently been revealed, corroborates the importance of BPs for neocortical expansion. Here, we argue that the morphology of BPs is a key cell biological basis for maintaining their high proliferative capacity and therefore plays crucial roles in the evolutionary expansion of the neocortex.
@article{Kalebic7749,
author={Nereo Kalebic, Wieland Huttner},
title={Basal Progenitor Morphology and Neocortex Evolution.},
journal ={Trends in neurosciences},
volume={},
pages={1--1},
year=2020
}