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| Open AccessMitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling
The pluripotent state of mouse embryonic stem cells (mESCs) is regulated by extrinsic and intrinsic signals but the underlying mechanisms are not completely understood. Here the authors show that the E3 ligase, March5, contributes to the maintenance of the pluripotent state in mESCs via suppression of ERK activation.
- Hao Gu
- , Qidong Li
- & Mian Wu
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Article
| Open AccessVimentin filament organization and stress sensing depend on its single cysteine residue and zinc binding
Vimentin is an intermediate filament protein that is targeted by oxidative modification at its single cysteine residue, C328. Here Pérez-Sala et al. reveal a role for this cysteine in vimentin organization and function, and uncover a protective role for zinc binding in filament stability.
- Dolores Pérez-Sala
- , Clara L. Oeste
- & F. Javier Cañada
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Article
| Open AccessDistinct domains in Bub1 localize RZZ and BubR1 to kinetochores to regulate the checkpoint
The spindle assembly checkpoint (SAC) depends on the recruitment of specific protein complexes to the kinetochore. Here Zhang et al. show that Bub1 recruits the RZZ complex and BubR1 to the kinetochore, and loss of the BubR1 binding sequence enhances checkpoint activity suggesting both SAC activating and silencing roles.
- Gang Zhang
- , Tiziana Lischetti
- & Jakob Nilsson
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Loss of kinesin-14 results in aneuploidy via kinesin-5-dependent microtubule protrusions leading to chromosome cut
Loss of the motor protein kinesin-14 can lead to aneuploidy, but the mechanism is not known. Here the authors show that loss of kinesin-14 in fission yeast leads to long spindle microtubule protrusions that push properly segregated chromosomes into the division site, leading to chromosome cut during cytokinesis.
- Viktoriya Syrovatkina
- & Phong T. Tran
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The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation
Multiple sclerosis is caused by autoreactive Th17 lymphocytes. Here the authors show that prostaglandin E2 promotes Th17 differentiation by activating transcription of IL-17 by CREB/CRTC2 complex, and that ablation of CRTC2 prevents Th17 differentiation and multiple sclerosis in a mouse model.
- Jeniffer B. Hernandez
- , Christina Chang
- & Marc Montminy
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Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2
The mechanisms regulating lymphatic vessel development and function are still largely unknown. Here, the authors show that the protein kinase Cdk5 is required for lymphatic vessel development by regulating the activity of the transcription factor Foxc2 and its target genes.
- Johanna Liebl
- , Siwei Zhang
- & Stefan Zahler
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Article
| Open AccessA negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling
The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization but little is known about the endogenous ligands that engage ErbB4 and the downstream targets. Here the authors describe the existence of a cell-autonomous bidirectional pathway that links NMDA receptor activity with NRG signalling in GABAergic interneurons.
- Detlef Vullhorst
- , Robert M. Mitchell
- & Andres Buonanno
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Article
| Open AccessPrmt5 is a regulator of muscle stem cell expansion in adult mice
Skeletal muscle satellite cells are important for muscle regeneration, but their regulatory mechanisms are largely unknown. Here the authors identify arginine methyltransferase Prmt5 as a key regulator of satellite cell maintenance and function in adult mice, and show that Prmt5 acts mainly but not exclusively on the cell cycle inhibitor p21.
- Ting Zhang
- , Stefan Günther
- & Thomas Braun
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Article
| Open AccessPlatelet actin nodules are podosome-like structures dependent on Wiskott–Aldrich syndrome protein and ARP2/3 complex
During early platelet spreading a novel F-actin structure forms, called the actin nodule. Here Poulter et al.demonstrate that actin nodule formation depends on WASp and the Arp2/3 complex, and using super-resolution microscopy they show that nodules bear a structural resemblance to podosomes.
- Natalie S. Poulter
- , Alice Y. Pollitt
- & Steven G. Thomas
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Article
| Open AccessCapping protein integrates multiple MAMP signalling pathways to modulate actin dynamics during plant innate immunity
Cytoskeletal remodelling is an important component of the innate immune response in plants. Here, Li et al. demonstrate that pathogen-triggered actin remodelling is due to the inhibition of capping protein (CP), and show that CP is required for resistance against plant pathogens.
- Jiejie Li
- , Jessica L. Henty-Ridilla
- & Christopher J. Staiger
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Article
| Open AccessAMPK activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation
Lipid droplets (LDs) supply fatty acids to cellular processes and move bidirectionally on microtubules. Here the authors show that nutrient starvation causes dispersal of mitochondria and LD to the periphery of the cell along detyrosinated microtubules and increases LD–mitochondria interactions in an AMPK-dependent manner.
- Albert Herms
- , Marta Bosch
- & Albert Pol
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Article
| Open AccessAcetylation of Beclin 1 inhibits autophagosome maturation and promotes tumour growth
Beclin 1 is an essential autophagy effector, necessary to form the autophagosome. Here Sun et al. show that Beclin 1 acetylation regulated by p300 and SIRT1 inhibits autophagosome maturation, and mutation of the acetylation sites leads to tumour growth suppression in vivo.
- Ting Sun
- , Xuan Li
- & Xiao-Feng Zhu
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Article
| Open AccessReal-time intermembrane force measurements and imaging of lipid domain morphology during hemifusion
During membrane fusion, lipid bilayers come into direct contact but rearrangements of lipid domains during fusion have not been thoroughly examined. Here the authors observe and correlate membrane morphology, interaction forces and domain rearrangements during hemifusion of two model membranes.
- Dong Woog Lee
- , Kai Kristiansen
- & Jacob N. Israelachvili
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Article
| Open AccessChemical synthesis of a two-photon-activatable chemokine and photon-guided lymphocyte migration in vivo
The precise spatiotemporal control of chemokine exposure would be an advantageous tool for immune cell research. Here, Chen et al. develop a two-photon-activatable chemokine CCL5 and use it to direct lymphocyte migration in vivo and to show that PI3-kinase is not required to sense a gradient in vitro.
- Xin Chen
- , Shan Tang
- & Hai Qi
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Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression
AF6, an essential protein for the organization of cell-to-cell junctions and development, is aberrantly expressed in several tumors but its role in pancreatic cancer is not clear. Here the authors show that in pancreatic cancer, loss of AF6 expression leads to induction of the EMT transcription factor Snail.
- Yi Xu
- , Renxu Chang
- & Lixing Zhan
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Article
| Open AccessIntracellular signalling and intercellular coupling coordinate heterogeneous contractile events to facilitate tissue folding
Epithelial sheet migration proceeds via a series of actomyosin contractions, called pulses, that are stabilized, or ratcheted. Here, Xie and Martin develop a computational framework to determine how pulses are coordinated, and show that ratcheting of pulses allows collective migration by preventing competition with neighbouring pulses.
- Shicong Xie
- & Adam C. Martin
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Article
| Open AccessMembrane tension controls the assembly of curvature-generating proteins
BAR domain proteins are known to reshape cell membranes. Using coarse-grained molecular dynamics simulations, Simunovic and Voth demonstrate that membrane tension strongly affects the association of BAR proteins, in turn controlling their recruitment to membrane-remodelling sites.
- Mijo Simunovic
- & Gregory A. Voth
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Article
| Open AccessPiezo1 ion channel pore properties are dictated by C-terminal region
Piezo ion channels function as mechanotransducers involved in vascular development and touch sensing, but their structural features remain unknown. Here the authors find that the C-terminal region of Piezo protein encompasses the pore and identify a glutamate residue within this region involved in ion conduction properties.
- Bertrand Coste
- , Swetha E. Murthy
- & Ardem Patapoutian
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Article
| Open AccessLAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation
Essential amino acids such as leucine activate mTORC1 signalling after entering the lysosome, but the molecular basis for lysosomal amino-acid uptake is unclear. Here Milkereit et al. show that LAPTM4b, a lysosomal membrane protein, recruits a leucine transporter to the lysosome and promotes amino-acid influx and mTORC1 signalling.
- Ruth Milkereit
- , Avinash Persaud
- & Daniela Rotin
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Article
| Open AccessPI3K/mTORC2 regulates TGF-β/Activin signalling by modulating Smad2/3 activity via linker phosphorylation
Although crosstalk between the phosphatidylinositol 3-kinase (PI3K) and transforming growth factor-β pathways is important, the mechanism is obscure. Here, Yu et al. show that activation of mTORC2 downstream of PI3K leads to the linker phosphorylation of Smad2/3 and their ubiquitin-dependent degradation.
- Jason S. L. Yu
- , Thamil Selvee Ramasamy
- & Wei Cui
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Article
| Open AccessPhotoswitchable fatty acids enable optical control of TRPV1
Fatty acids are ancient lipids with numerous functions, from metabolic processes as a source of energy to structural and signalling roles within cell membranes. Here, the authors present azobenzene-modified fatty acids and their application as photoswitchable agonists of the Vanilloid Receptor 1.
- James Allen Frank
- , Mirko Moroni
- & Dirk Trauner
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Article
| Open AccessSingle-molecule imaging of a three-component ordered actin disassembly mechanism
The roles of Coronin, Cofilin and AIP1 in promoting actin disassembly have not been well understood. Here using single-molecule fluorescence imaging, Jansen et al. show that the three proteins act together in a coordinated, temporal pathway to induce rapid severing and disassembly of actin filaments.
- Silvia Jansen
- , Agnieszka Collins
- & Bruce L. Goode
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The oncogenic microRNA miR-21 promotes regulated necrosis in mice
The microRNA miR-21 is overexpressed in cancer and is thought to function through anti-apoptotic activity. Here, Ma et al. show that deleting or blocking miR-21 in mice protects against acute pancreatitis and TNF-α-induced tissue damage by inhibiting RIP3-dependent regulated necrosis (necroptosis).
- Xiaodong Ma
- , Daniel J. Conklin
- & Yong Li
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Article
| Open AccessThe fission yeast MTREC complex targets CUTs and unspliced pre-mRNAs to the nuclear exosome
The evolutionarily conserved MTREC complex promotes degradation of meiotic mRNAs and regulatory ncRNAs. Here the authors show that MTREC also targets cryptic unstable transcripts and unspliced pre-mRNAs for degradation by the nuclear exosome, while the TRAMP complex has only a minor role in this process.
- Yang Zhou
- , Jianguo Zhu
- & Tamás Fischer
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Article
| Open AccessC8orf4 negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signalling
Cancer stem cells are a small proportion of tumours that often confer resistance to chemotherapy but how these cells are maintained is unclear. Here, Zhu et al. study hepatocellular carcinoma stem cells and identify C8orf4 as a negative regulator of Notch2, which is required for the self-renewal of the cells.
- Pingping Zhu
- , Yanying Wang
- & Zusen Fan
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Article
| Open AccessExposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin
The reparative capacity of tissues decreases with age. Here, Baht et al. perform parabiosis experiments and provide evidence for the existence of a soluble factor produced by young, but not old, haematopoietic cells that is capable of improving fracture repair in old mice.
- Gurpreet S. Baht
- , David Silkstone
- & Benjamin A. Alman
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Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis
Chronic pancreatitis is an inflammatory disease accompanied by fibrosis. Here the authors show that pancreatic stellate cells produce IL-4 and IL-13 that trigger alternative activation of macrophages, and that genetic or pharmacological inhibition of IL-4/IL-13 signaling ameliorates the disease.
- Jing Xue
- , Vishal Sharma
- & Aida Habtezion
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Editing the genome to introduce a beneficial naturally occurring mutation associated with increased fetal globin
Adult expression of fetal haemoglobin is beneficial and thus desirable in patients with haemoglobin disorders. Here the authors introduce a naturally occurring mutation in the γ-globinpromoter and show that it causes binding of an activator TAL1, chromosome looping and revival of fetal haemoglobin expression in erythroid cells.
- Beeke Wienert
- , Alister P. W. Funnell
- & Merlin Crossley
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Article
| Open AccessDirectional cell movement through tissues is controlled by exosome secretion
How cells maintain directional polarity when migrating through a complex environment is not well understood. Here Sung et al. show that autocrine exosome secretion is required for persistent and efficient in vivocancer cell motility and promotes assembly of adhesion complexes by delivering fibronectin-bound exosomes.
- Bong Hwan Sung
- , Tatiana Ketova
- & Alissa M. Weaver
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The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells
Colitis is a common human disorder but the clinical interventions are limited as the pathological mechanisms are not very clear. Here the authors find an elevated expression of non-muscle-myosin-II heavy chain Myh9 in a colitis mouse model, and show that Myh9 expression reduction or activity inhibition ameliorates epithelial injuries.
- Bing Zhao
- , Zhen Qi
- & Ye-Guang Chen
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Article
| Open AccessVisualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters
Extracellular vesicles (EVs) act as a conduit for intercellular communication through the exchange of cellular materials without direct cell-to-cell contacts. Here the authors develop a multiplexed reporter system that allows monitoring of EV exchange, cargo delivery and protein translation between different cell populations.
- Charles P. Lai
- , Edward Y. Kim
- & Xandra O. Breakefield
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Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity
The presence of lymph node-like vasculature in tumours correlates with positive prognosis, but the mechanisms by which it forms and affects tumour growth are unclear. Here the authors show that it is induced by CD8 and NK cells, and supports naive T cells’ differentiation into antitumour effectors.
- J. David Peske
- , Elizabeth D. Thompson
- & Victor H. Engelhard
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Article
| Open AccessReinforcement of STAT3 activity reprogrammes human embryonic stem cells to naive-like pluripotency
LIF/STAT3 signalling characterizes naive pluripotency in mouse embryonic stem cells (ESCs), but whether this pathway can sustain a similar state in human cells is not completely understood. Here the authors show that LIF stimulation and enhancement of STAT3 activity allow human ESCs to escape from FGF2 dependency and facilitates their entry into a naive-like state of pluripotency.
- Hongwei Chen
- , Irène Aksoy
- & Pierre Savatier
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Article
| Open AccessNeuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2
Neurons in the brain are more susceptible to oxidative stress than astroglial cells but the molecular basis and biological reasons for this are poorly understood. Here the authors show that developing cortical neurons have reduced levels of the antioxidant transcription factor Nrf2 due to epigenetic silencing and that this is necessary for proper neuronal development.
- Karen F.S. Bell
- , Bashayer Al-Mubarak
- & Giles E. Hardingham
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Article
| Open AccessThe structure of FMNL2–Cdc42 yields insights into the mechanism of lamellipodia and filopodia formation
FMNL formins polymerize actin filaments to generate cellular protrusions such as lamellipodia and filopodia at the leading edge of a cell. Here the authors provide detailed mechanistic insights into the formation of actin-based protrusions through GTPase dependent activation and membrane localization of FMNL1 and FMNL2.
- Sonja Kühn
- , Constanze Erdmann
- & Matthias Geyer
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Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2
Angiogenesis is regulated by dynamic changes in endothelial cell contact. Here, the authors show that signals from endothelial cell junctions affect the subcellular localization and function of Yes-associated protein, ultimately modifying angiopoietin-2 expression and angiogenic activity of endothelial cells.
- Hyun-Jung Choi
- , Haiying Zhang
- & Young-Guen Kwon
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Article
| Open AccessAnammox Planctomycetes have a peptidoglycan cell wall
Planctomycetes are unusual bacteria with complex intracellular compartments and an apparent lack of peptidoglycan in their cell walls. Here, van Teeseling et al. show that the cell wall of an anammox planctomycete does contain peptidoglycan, and propose to redefine planctomycetes as Gram-negative bacteria.
- Muriel C.F. van Teeseling
- , Rob J. Mesman
- & Laura van Niftrik
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Article
| Open AccessSingle-molecule super-resolution imaging of chromosomes and in situ haplotype visualization using Oligopaint FISH probes
The spatial organization of the genome within the nucleus impacts many processes. Here the authors combine oligo-based DNA FISH with single-molecule super-resolution microscopy to image single-copy genomic regions and, taking advantage of SNPs, distinguish allelic regions of homologous chromosomes.
- Brian J. Beliveau
- , Alistair N. Boettiger
- & Chao-ting Wu
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Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo
Insulin and the transcription factor FoxO1 are key regulators of hepatic glucose metabolism. Here, Titchenell et al. provide evidence for the existence of an insulin-dependent extrahepatic pathway that is fully capable of regulating hepatic glucose production in the absence of hepatic FoxO1.
- Paul M. Titchenell
- , Qingwei Chu
- & Morris J. Birnbaum
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Article
| Open AccessPlanctomycetes do possess a peptidoglycan cell wall
Planctomycetes appear to differ from all other bacteria in their cellular organization and their apparent lack of a peptidoglycan (PG) cell wall. Here Jeske et al. show that Planctomycetes do possess a typical PG cell wall and that their cellular architecture resembles that of Gram-negative bacteria.
- Olga Jeske
- , Margarete Schüler
- & Christian Jogler
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Article
| Open AccessType II spiral ganglion afferent neurons drive medial olivocochlear reflex suppression of the cochlear amplifier
The medial olivocochlear efferent reflex regulates cochlear outer hair cell-based amplification of sound energy. Here the authors show this dynamic control of hearing sensitivity is driven by sensory input from the outer hair cells and their type II spiral ganglion neuron innervation.
- Kristina E. Froud
- , Ann Chi Yan Wong
- & Gary D. Housley
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FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization
Insulin and the transcription factor FoxO1 are key regulators of glucose metabolism. Using mice that lack insulin receptor and FoxO1 in the liver, O-Sullivan et al.show that extrahepatic effects of insulin are sufficient to maintain glucose homeostasis when hepatic FoxO1 is disrupted.
- InSug O-Sullivan
- , Wenwei Zhang
- & Terry G. Unterman
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Article
| Open AccessConformational rearrangements in the transmembrane domain of CNGA1 channels revealed by single-molecule force spectroscopy
Cyclic nucleotide gated channels are activated after binding cyclic nucleotides. Here, using single molecule force spectroscopy, the authors reveal that cyclic nucleotide binding causes conformational changes and tighter coupling of the S4 helix to the pore forming domain.
- Sourav Maity
- , Monica Mazzolini
- & Vincent Torre
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Article
| Open AccessAutophagosome–lysosome fusion is independent of V-ATPase-mediated acidification
BafilomycinA1 is an autophagy inhibitor, presumably owing to its blocking effect on the lysosomal proton pump V-ATPase. Here the authors show that V-ATPase-deficient lysosomes can still fuse with autophagosomes, showing that lysosomal acidification and fusion are two separable, independent events.
- Caroline Mauvezin
- , Péter Nagy
- & Thomas P. Neufeld
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Degradation of Ndd1 by APC/CCdh1 generates a feed forward loop that times mitotic protein accumulation
Ndd1 activates the transcription of mitotic regulators. Here the authors show that the ubiquitin ligase complex APC/CCdh1ubiquitinates Ndd1 as well as Ndd1 target genes, creating a feedforward loop that generates an early class of substrates that accumulate at S phase and a late class that accumulate at G2.
- Julia Sajman
- , Drora Zenvirth
- & Michael Brandeis
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Article
| Open AccessCells change their sensitivity to an EGF morphogen gradient to control EGF-induced gene expression
How morphogen gradients induce complex gene expression programmes in the receiving cells is poorly understood. Here the authors use a quantitative approach to show that inC. elegansvulva induction cells control morphogen-induced gene expression by changing their sensitivity to the morphogen.
- Jeroen Sebastiaan van Zon
- , Simone Kienle
- & Alexander van Oudenaarden
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Commissural axonal corridors instruct neuronal migration in the mouse spinal cord
During vertebrate embryogenesis, migration of neuronal cell bodies and axons occurs simultaneously, but to what degree they influence each other’s development remains unclear. Here the authors find that in the mouse spinal cord commissural axons influence neuronal migration in two different ways.
- Christophe Laumonnerie
- , Yong Guang Tong
- & Sara I. Wilson
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Article
| Open AccessNon-autonomous DAF-16/FOXO activity antagonizes age-related loss of C. elegans germline stem/progenitor cells
The number of germline stem/progenitor cells in C. elegansdeclines with age. Here the authors show this cell loss is mediated by the transcription factor DAF-16/FOXO acting in specific somatic gonad cells, demonstrating that stem cell aging can be anatomically uncoupled from organismal aging.
- Zhao Qin
- & E. Jane Albert Hubbard
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Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation
The inflammasomes are multiprotein structures that trigger inflammation in response to diverse stress conditions. Here, Ip and Medzhitov show that the NLRP3 and NLRC4 inflammasomes in macrophages act as sensors of hyperosmotic stress and participate in salt-induced inflammatory responses.
- W. K. Eddie Ip
- & Ruslan Medzhitov
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