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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
}

SoRi Jang, Zhao Xuan, Ross C Lagoy, Louise Jawerth, Ian J Gonzalez, Milind Singh, Shavanie Prashad, Hee Soo Kim, Avinash Patel, Dirk R Albrecht, Anthony Hyman, Daniel A Colón-Ramos
Phosphofructokinase Relocalizes into Subcellular Compartments with Liquid-like Properties In Vivo.
Biophys J, Art. No. doi: 10.1016/j.bpj.2020.08.002 (2020)
PubMed Source   

Although much is known about the biochemical regulation of glycolytic enzymes, less is understood about how they are organized inside cells. We systematically examine the dynamic subcellular localization of glycolytic protein phosphofructokinase-1/PFK-1.1 in Caenorhabditis elegans. We determine that endogenous PFK-1.1 localizes to subcellular compartments in vivo. In neurons, PFK-1.1 forms phase-separated condensates near synapses in response to energy stress from transient hypoxia. Restoring animals to normoxic conditions results in cytosolic dispersion of PFK-1.1. PFK-1.1 condensates exhibit liquid-like properties, including spheroid shapes due to surface tension, fluidity due to deformations, and fast internal molecular rearrangements. Heterologous self-association domain cryptochrome 2 promotes formation of PFK-1.1 condensates and recruitment of aldolase/ALDO-1. PFK-1.1 condensates do not correspond to stress granules and might represent novel metabolic subcompartments. Our studies indicate that glycolytic protein PFK-1.1 can dynamically form condensates in vivo.
@article{Jang7751,
author={SoRi Jang, Zhao Xuan, Ross C Lagoy, Louise Jawerth, Ian J Gonzalez, Milind Singh, Shavanie Prashad, Hee Soo Kim, Avinash Patel, Dirk R Albrecht, Anthony Hyman, Daniel A Colón-Ramos},
title={Phosphofructokinase Relocalizes into Subcellular Compartments with Liquid-like Properties In Vivo.},
journal ={Biophysical journal},
volume={},
pages={1--1},
year=2020
}

Vamshidhar Gade, Sofia Traikov, Jana Oertel, Karim Fahmy, Teymuras V. Kurzchalia
C. elegans possess a general program to enter cryptobiosis that allows dauer larvae to survive different kinds of abiotic stress.
Sci Rep, 10(1) Art. No. 13466 (2020)
PubMed Source   

All organisms encounter abiotic stress but only certain organisms are able to cope with extreme conditions and enter into cryptobiosis (hidden life). Previously, we have shown that C. elegans dauer larvae can survive severe desiccation (anhydrobiosis), a specific form of cryptobiosis. Entry into anhydrobiosis is preceded by activation of a set of biochemical pathways by exposure to mild desiccation. This process called preconditioning induces elevation of trehalose, intrinsically disordered proteins, polyamines and some other pathways that allow the preservation of cellular functionality in the absence of water. Here, we demonstrate that another stress factor, high osmolarity, activates similar biochemical pathways. The larvae that acquired resistance to high osmotic pressure can also withstand desiccation. In addition, high osmolarity significantly increases the biosynthesis of glycerol making larva tolerant to freezing. Thus, to survive abiotic stress, C. elegans activates a combination of genetic and biochemical pathways that serve as a general survival program.
@article{Gade7734,
author={Vamshidhar Gade, Sofia Traikov, Jana Oertel, Karim Fahmy, Teymuras V. Kurzchalia},
title={C. elegans possess a general program to enter cryptobiosis that allows dauer larvae to survive different kinds of abiotic stress.},
journal ={Scientific reports},
volume={10},
issue ={1},
pages={null--null},
year=2020
}

Laura Christin Trautenberg, Oskar Knittelfelder, Carla Hofmann, Andrej Shevchenko, Marko Brankatschk, Elodie Prince
How to use the development of individual Drosophila larvae as a metabolic sensor.
J. Insect Physiol., Art. No. doi: 10.1016/j.jinsphys.2020.104095 (2020)
PubMed Source   

Metabolic research is a challenge because of the variety of data within experimental series and the difficulty of replicating results among scientific groups. The fruit fly, Drosophila melanogaster, is a cost-effective and reliable pioneer model to screen dietary variables for metabolic research. One of the main reasons for problems in this field are differences in food recipes, diet-associated microbial environments and the pharmacokinetic behavior of nutrients across the gut-blood barrier. To prevent such experimental shortcomings, a common strategy is to pool scores of subjects into one sample to create an average statement. However, this approach lacks information about the biological spread and may provoke misleading interpretations. We propose to use the developmental rate of individual Drosophila larvae as a metabolic sensor. To do so, we introduce here a 96-well plate-based assay, which allows screening for multiple variables including food quality, microbial load, and genetic differences. We demonstrate that on a diet that is rich in calories, pupation is sensitive to the variation of dietary lipid compounds and that genotypes considered as wild-types/controls produce different developmental profiles. Our platform is suited for later automation and represents a potent high-throughput screening tool for the pharmacology and food industry. If used systematically, our assay could become a powerful reference tool to compare the quality of used dietary configurations with published benchmark recipes.
@article{Trautenberg7733,
author={Laura Christin Trautenberg, Oskar Knittelfelder, Carla Hofmann, Andrej Shevchenko, Marko Brankatschk, Elodie Prince},
title={How to use the development of individual Drosophila larvae as a metabolic sensor.},
journal ={Journal of insect physiology},
volume={},
pages={104095--104095},
year=2020
}

Nandini Asokan, Stephan Daetwyler, Stefanie N Bernas, Christopher Schmied, Steffen Vogler, Katrin Lambert, Manja Wobus, Martin Wermke, Gerd Kempermann, Jan Huisken, Michael Brand, Martin Bornhäuser
Long-term in vivo imaging reveals tumor-specific dissemination and captures host tumor interaction in zebrafish xenografts.
Sci Rep, 10(1) Art. No. 13254 (2020)
PubMed Source   

Understanding mechanisms mediating tumor metastasis is crucial for diagnostic and therapeutic targeting. Here, we take advantage of a transparent embryonic zebrafish xenograft model (eZXM) to visualize and track metastatic cells in real time using selective plane illumination microscopy (SPIM) for up to 30 h. Injected human leukemic and breast cancer cells exhibited cell-type specific patterns of intravascular distribution with leukemic cells moving faster than breast cancer cells. Tracking of tumor cells from high-resolution images revealed acute differences in intravascular speed and distance covered by cells. While the majority of injected breast cancer cells predominantly adhered to nearby vasculature, about 30% invaded the non-vascularized tissue, reminiscent of their metastatic phenotype. Survival of the injected tumor cells appeared to be partially inhibited and time-lapse imaging showed a possible role for host macrophages of the recipient embryos. Leukemic cell dissemination could be effectively blocked by pharmacological ROCK1 inhibition using Fasudil. These observations, and the ability to image several embryos simultaneously, support the use of eZXM and SPIM imaging as a functional screening platform to identify compounds that suppress cancer cell spread and invasion.
@article{Asokan7727,
author={Nandini Asokan, Stephan Daetwyler, Stefanie N Bernas, Christopher Schmied, Steffen Vogler, Katrin Lambert, Manja Wobus, Martin Wermke, Gerd Kempermann, Jan Huisken, Michael Brand, Martin Bornhäuser},
title={Long-term in vivo imaging reveals tumor-specific dissemination and captures host tumor interaction in zebrafish xenografts.},
journal ={Scientific reports},
volume={10},
issue ={1},
pages={null--null},
year=2020
}