Nicolas Loyer, Elizabeth K J Hogg, Hayley G Shaw, Anna Pasztor, David H Murray, Greg M Findlay, Jens Januschke
The generation of distinct cell fates during development depends on asymmetric cell division of progenitor cells. In the central and peripheral nervous system of Drosophila , progenitor cells respectively called neuroblasts or sensory organ precursors use PAR polarity during mitosis to control cell fate determination in their daughter cells. How polarity and the cell cycle are coupled, and how the cell cycle machinery regulates PAR protein function and cell fate determination is poorly understood. Here, we generate an analog sensitive allele of CDK1 and reveal that its partial inhibition weakens but does not abolish apical polarity in embryonic and larval neuroblasts and leads to defects in polarisation of fate determinants...
June 13, 2024: ELife
Melody C Iacino, Taylor A Stowe, Elizabeth G Pitts, Lacey L Sexton, Shannon L Macauley, Mark J Ferris
Adolescence is characterized by changes in reward-related behaviors, social behaviors, and decision making. These behavioral changes are necessary for the transition into adulthood, but they also increase vulnerability to the development of a range of psychiatric disorders. Major reorganization of the dopamine system during adolescence is thought to underlie, in part, the associated behavioral changes and increased vulnerability. Here, we utilized fast scan cyclic voltammetry and microdialysis to examine differences in dopamine release as well as mechanisms that underlie differential dopamine signaling in the nucleus accumbens (NAc) core of adolescent (P28-35) and adult (P70-90) male rats...
June 11, 2024: ELife
Thomas Morgan Li, Victoria Zyulina, Ethan S Seltzer, Marija Dacic, Yurii Chinenov, Andrea R Daamen, Keila R Veiga, Noa Schwartz, David J Oliver, Pamela Cabahug-Zuckerman, Jose Lora, Yong Liu, William D Shipman, William G Ambler, Sarah F Taber, Karen B Onel, Jonathan H Zippin, Mehdi Rashighi, James G Krueger, Niroshana Anandasabapathy, Inez Rogatsky, Ali Jabbari, Carl P Blobel, Peter E Lipsky, Theresa T Lu
The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers...
June 11, 2024: ELife
Youjia Guo, Tomohiro Kitano, Kimiko Inoue, Kensaku Murano, Michiko Hirose, Ten D Li, Akihiko Sakashita, Hirotsugu Ishizu, Narumi Ogonuki, Shogo Matoba, Masayuki Sato, Atsuo Ogura, Haruhiko Siomi
Once fertilized, mouse zygotes rapidly proceed to zygotic genome activation (ZGA), during which long terminal repeats (LTRs) of murine endogenous retroviruses with leucine tRNA primer (MERVL) are activated by a conserved homeodomain-containing transcription factor, DUX. However, Dux -knockout embryos produce fertile mice, suggesting that ZGA is redundantly driven by an unknown factor(s). Here we present multiple lines of evidence that the multicopy homeobox gene, Obox4 , encodes a transcription factor that is highly expressed in mouse 2-cell embryos and redundantly drives ZGA...
June 10, 2024: ELife
Kevin P Koster, S Murray Sherman
A key to motor control is the motor thalamus, where several inputs converge. One excitatory input originates from layer 5 of primary motor cortex (M1L5 ), while another arises from the deep cerebellar nuclei (Cb). M1L5 terminals distribute throughout the motor thalamus and overlap with GABAergic inputs from the basal ganglia output nuclei, the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNr). In contrast, it is thought that Cb and basal ganglia inputs are segregated. Therefore, we hypothesized that one potential function of the GABAergic inputs from basal ganglia is to selectively inhibit, or gate, excitatory signals from M1L5 in the motor thalamus...
June 10, 2024: ELife
Mayank Verma, Yoko Asakura, Xuerui Wang, Kasey Zhou, Mahmut Ünverdi, Allison P Kann, Robert S Krauss, Atsushi Asakura
Endothelial and skeletal muscle lineages arise from common embryonic progenitors. Despite their shared developmental origin, adult endothelial cells (ECs) and muscle stem cells (MuSCs) (satellite cells) have been thought to possess distinct gene signatures and signaling pathways. Here we shift this paradigm by uncovering how adult MuSC behavior is affected by the expression of a subset of EC transcripts. We used several computational analyses including single-cell RNAseq to show that MuSCs express low levels of canonical EC markers in mice...
June 6, 2024: ELife
Thierry Gilbert, Camille Gorlt, Merlin Barbier, Benjamin Duployer, Marianna Plozza, Ophélie Dufrancais, Laure-Elene Martet, Elisa Dalbard, Loelia Segot, Christophe Tenailleau, Laurence Haren, Christel Vérollet, Christiane Bierkamp, Andreas Merdes
Ninein is a centrosome protein that has been implicated in microtubule anchorage and centrosome cohesion. Mutations in the human NINEIN gene have been linked to Seckel syndrome and to a rare form of skeletal dysplasia. However, the role of ninein in skeletal development remains unknown. Here, we describe a ninein knockout mouse with advanced endochondral ossification during embryonic development. Although the long bones maintain a regular size, the absence of ninein delays the formation of the bone marrow cavity in the prenatal tibia...
June 5, 2024: ELife
Yannick Schäfer, Katja Palitzsch, Maria Leptin, Andrew R Whiteley, Thomas Wiehe, Jaanus Suurväli
Copy number variation in large gene families is well characterized for plant resistance genes, but similar studies are rare in animals. The zebrafish ( Danio rerio ) has hundreds of NLR immune genes, making this species ideal for studying this phenomenon. By sequencing 93 zebrafish from multiple wild and laboratory populations we identified a total of 1,513 NLRs, many more than the previously known 400. Approximately half of those are present in all wild populations, but only 4% were found in 80% or more of the individual fish...
June 4, 2024: ELife
Samuel C Griffiths, Jia Tan, Armin Wagner, Levi L Blazer, Jarret J Adams, Srisathya Srinivasan, Shayan Moghisaei, Sachdev S Sidhu, Christian Siebold, Hsin-Yi Henry Ho
The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, Brachydactyly B and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine-rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of ligand reception...
May 23, 2024: ELife
Amanda Chu, Nicholas T Gordon, Aleah M DuBois, Christa B Michel, Katherine E Hanrahan, David C Williams, Stefano Anzellotti, Michael A McDannald
Pavlovian fear conditioning has been extensively used to study the behavioral and neural basis of defensive systems. In a typical procedure, a cue is paired with foot shock, and subsequent cue presentation elicits freezing, a behavior theoretically linked to predator detection. Studies have since shown a fear conditioned cue can elicit locomotion, a behavior that - in addition to jumping, and rearing - is theoretically linked to imminent or occurring predation. A criticism of studies observing fear conditioned cue-elicited locomotion is that responding is non-associative...
May 21, 2024: ELife
Maksim Kleverov, Daria Zenkova, Vladislav Kamenev, Margarita Sablina, Maxim N Artyomov, Alexey A Sergushichev
Transcriptomic profiling became a standard approach to quantify a cell state, which led to accumulation of huge amount of public gene expression datasets. However, both reuse of these datasets or analysis of newly generated ones requires significant technical expertise. Here we present Phantasus - a user-friendly web-application for interactive gene expression analysis which provides a streamlined access to more than 96000 public gene expression datasets, as well as allows analysis of user-uploaded datasets...
May 14, 2024: ELife
Pascal Forcella, Niklas Ifflander, Chiara Rolando, Elli-Anna Balta, Aikaterini Lampada, Claudio Giachino, Tanzila Mukhtar, Thomas Bock, Verdon Taylor
Neural stem cells (NSCs) are multipotent and correct fate determination is crucial to guarantee brain formation and homeostasis. How NSCs are instructed to generate neuronal or glial progeny is not well understood. Here we addressed how murine adult hippocampal NSC fate is regulated and describe how Scaffold Attachment Factor B (SAFB) blocks oligodendrocyte production to enable neuron generation. We found that SAFB prevents NSC expression of the transcription factor Nuclear Factor I/B (NFIB) by binding to sequences in the Nfib mRNA and enhancing Drosha-dependent cleavage of the transcripts...
May 9, 2024: ELife
Rupam Choudhury, Anuroop Venkateswaran Venkatasubramani, Jie Hua, Marco Borsò, Celeste Franconi, Sarah Kinkley, Ignasi Forné, Axel Imhof
Eukaryotic chromatin is organized into functional domains, that are characterized by distinct proteomic compositions and specific nuclear positions. In contrast to cellular organelles surrounded by lipid membranes, the composition of distinct chromatin domains is rather ill described and highly dynamic. To gain molecular insight into these domains and explore their composition, we developed an antibody-based proximity-biotinylation method targeting the RNA and proteins constituents. The method that we termed Antibody-Mediated-Proximity-Labelling-coupled to Mass Spectrometry (AMPL-MS) does not require the expression of fusion proteins and therefore constitutes a versatile and very sensitive method to characterize the composition of chromatin domains based on specific signature proteins or histone modifications...
May 8, 2024: ELife
Savvas Nikolaou, Amelie Juin, Jamie A Whitelaw, Nikki R Paul, Loic Fort, Colin Nixon, Heather J Spence, Sheila Bryson, Laura M Machesky
Pancreatic ductal adenocarcinoma carries a dismal prognosis, with high rates of metastasis and few treatment options. Hyperactivation of KRAS in almost all tumours drives RAC1 activation, conferring enhanced migratory and proliferative capacity as well as macropinocytosis. Macropinocytosis is well understood as a nutrient scavenging mechanism, but little is known about its functions in trafficking of signaling receptors. We find that CYRI-B is highly expressed in pancreatic tumours in a mouse model of KRAS and p53-driven pancreatic cancer...
May 7, 2024: ELife
Matthew F Wipperman, Allen Z Lin, Kaitlyn M Gayvert, Benjamin Lahner, Selin Somersan-Karakaya, Xuefang Wu, Joseph Im, Minji Lee, Bharatkumar Koyani, Ian Setliff, Malika Thakur, Daoyu Duan, Aurora Breazna, Fang Wang, Wei Keat Lim, Gabor Halasz, Jacek Urbanek, Yamini Patel, Gurinder S Atwal, Jennifer D Hamilton, Samuel Stuart, Oren Levy, Andreja Avbersek, Rinol Alaj, Sara C Hamon, Olivier Harari
Gait is impaired in musculoskeletal conditions, such as knee arthropathy. Gait analysis is used in clinical practice to inform diagnosis and to monitor disease progression or intervention response. However, clinical gait analysis relies on subjective visual observation of walking, as objective gait analysis has not been possible within clinical settings due to the expensive equipment, large-scale facilities, and highly trained staff required. Relatively low-cost wearable digital insoles may offer a solution to these challenges...
April 30, 2024: ELife
Amirhossein Farzmahdi, Wilbert Zarco, Winrich A Freiwald, Nikolaus Kriegeskorte, Tal Golan
Primates can recognize objects despite 3D geometric variations such as in-depth rotations. The computational mechanisms that give rise to such invariances are yet to be fully understood. A curious case of partial invariance occurs in the macaque face-patch AL and in fully connected layers of deep convolutional networks in which neurons respond similarly to mirror-symmetric view (e.g., left and right profiles). Why does this tuning develop? Here, we propose a simple learning-driven explanation for mirror-symmetric viewpoint tuning...
April 25, 2024: ELife
Mariana I Tsap, Andriy S Yatsenko, Jan Hegermann, Bibiana Beckmann, Dimitros Tsikas, Halyna R Shcherbata
Mutations in Drosophila Swiss Cheese (SWS) gene or its vertebrate orthologue Neuropathy Target Esterase (NTE) lead to progressive neuronal degeneration in flies and humans. Despite its enzymatic function as a phospholipase is well-established, the molecular mechanism responsible for maintaining nervous system integrity remains unclear. In this study, we found that NTE/SWS is present in surface glia that forms the blood-brain-barrier (BBB) and that NTE/SWS is important to maintain its structure and permeability...
April 25, 2024: ELife
Aedan Yue Li, Natalia Ladyka-Wojcik, Heba Qazilbash, Ali Golestani, Dirk Bernhardt-Walther, Chris B Martin, Morgan Barense
Combining information from multiple senses is essential to object recognition, core to the ability to learn concepts, make new inferences, and generalize across distinct entities. Yet how the mind combines sensory input into coherent crossmodal representations - the crossmodal binding problem - remains poorly understood. Here, we applied multi-echo fMRI across a four-day paradigm, in which participants learned 3-dimensional crossmodal representations created from well-characterized unimodal visual shape and sound features...
April 22, 2024: ELife
Natalia Dolgova, Eva-Maria E Uhlemann, Michal T Boniecki, Frederick S Vizeacoumar, Anjuman Ara, Paria Nouri, Martina Ralle, Marco Tonelli, Syed A Abbas, Jaala Patry, Hussain Elhasasna, Andrew Freywald, Franco Vizeacoumar, Oleg Y Dmitriev
Mediator of ERBB2-driven Cell Motility 1 (MEMO1) is an evolutionary conserved protein implicated in many biological processes; however, its primary molecular function remains unknown. Importantly, MEMO1 is overexpressed in many types of cancer and was shown to modulate breast cancer metastasis through altered cell motility. To better understand the function of MEMO1 in cancer cells, we analyzed genetic interactions of MEMO1 using gene essentiality data from 1028 cancer cell lines and found multiple iron-related genes exhibiting genetic relationships with MEMO1...
April 19, 2024: ELife
Moagi Tube Shaku, Peter K Um, Karl L Ocius, Alexis J Apostolos, Marcos M Pires, William R Bishai, Bavesh D Kana
Mechanisms by which Mycobacterium tuberculosis (Mtb) evades pathogen recognition receptor activation during infection may offer insights for the development of improved tuberculosis (TB) vaccines. Whilst Mtb elicits NOD-2 activation through host recognition of its peptidoglycan-derived muramyl dipeptide (MDP), it masks the endogenous NOD-1 ligand through amidation of glutamate at the second position in peptidoglycan side-chains. As the current BCG vaccine is derived from pathogenic mycobacteria, a similar situation prevails...
April 19, 2024: ELife
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