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| Open AccessSequential actions of β-catenin and Bmp pattern the oral nerve net in Nematostella vectensis
The bilaterian central nervous system is thought to have evolved from a cnidarian-like ancestor, but the mechanisms of neural induction in cnidarians are largely unknown. Here the authors study the cnidarian Nematostella vectensisand show that β-catenin signalling is crucial for the early induction of its embryonic nervous system, suggesting evolutionary roots for this pathway.
- Hiroshi Watanabe
- , Anne Kuhn
- & Thomas W. Holstein
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Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation
The histone demethylase Jmjd3 is involved in many biological processes. Here, the authors generate T cell-specific Jmjd3-deficient mice and show that Jmjd3 has a role in T-cell function and in the differentiation and interconversion of T-cell subsets in the intestine.
- Qingtian Li
- , Jia Zou
- & Rong-Fu Wang
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Article
| Open AccessThe Escherichia coli effector EspJ blocks Src kinase activity via amidation and ADP ribosylation
Non-receptor tyrosine kinases such as Src play fundamental roles in host–pathogen interactions and phagocytosis. Here, Young et al. show that an enteropathogenic Escherichia coli(EPEC) protein, EspJ, inhibits Src activity by simultaneous amidation and ADP ribosylation of a conserved residue on the kinase.
- Joanna C. Young
- , Abigail Clements
- & Gad Frankel
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A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder
Multiple sulfatase deficiency is a lysosomal storage disorder arising from mutations in the sulfatase modifying factor 1 (SUMF1) gene. Here Frankel et al. show that targeting a microRNA, miR-95, can increase residual SUMF1 expression and restore sulfatase activity in patient cells.
- Lisa B. Frankel
- , Chiara Di Malta
- & Anders H. Lund
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Article
| Open AccessThe tumour suppressor DLC2 ensures mitotic fidelity by coordinating spindle positioning and cell–cell adhesion
Epithelial cells must position their mitotic spindle correctly to maintain cell–cell adhesion. Here Vitiello et al. show that the tumour suppressor DLC2 and the mitotic kinesin Kif1b coordinate microtubule–actin interactions upstream of mDia3, guiding spindle positioning and mitotic fidelity.
- Elisa Vitiello
- , Jorge G. Ferreira
- & Karl Matter
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Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction
Short telomeres are risk factors for age-associated diseases such as cardiopathies. Here the authors show that cardiac reactivation of telomerase, the telomere-elongating enzyme whose expression is normally silenced postnatally, mitigates the consequences of myocardial infarction in adult mice.
- Christian Bär
- , Bruno Bernardes de Jesus
- & Maria A. Blasco
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Article
| Open AccessLive-cell multiplane three-dimensional super-resolution optical fluctuation imaging
Super-resolution optical fluctuation imaging provides 3D images of biological specimens via blinking fluorophores. Geissbuehler et al. present a multiplexed version of this method that captures images at multiple focal planes simultaneously, reducing the acquisition time compared with standard approaches.
- Stefan Geissbuehler
- , Azat Sharipov
- & Marcel Leutenegger
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Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion
Integrins are activated by binding to the cytoskeletal adaptor talin, but the mechanisms guiding activation are unclear. Here Yang et al.show that the Rap1 effector RIAM binds to the integrin-binding head of talin to promote integrin activation, perhaps by sterically interfering with talin autoinhibition.
- Jun Yang
- , Liang Zhu
- & Jun Qin
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Article
| Open AccessA molecular toggle after exocytosis sequesters the presynaptic syntaxin1a molecules involved in prior vesicle fusion
Synaptic vesicle fusion involves a multi-protein assembly called the SNARE complex that is tightly regulated both spatially and temporally. Here Kavanagh et al. show that after vesicle fusion and SNARE complex disassembly in the synapse, the SNARE protein syntaxin1a is sequestered in a monomeric form by munc18-1, preventing ectopic SNARE complex assembly.
- Deirdre M. Kavanagh
- , Annya M. Smyth
- & Rory R. Duncan
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Article
| Open AccessThe switching role of β-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes
The contribution of signal strength on cell fate decisions is often not reflected in signalling networks. By combining mathematical simulation and biochemical experiments in cultured adult cardiomyocytes, Shin et al. show that the concentration of a β-adrenergic receptor agonist affects the expression of Bcl-2, influencing the balance between cell survival and death.
- Sung-Young Shin
- , Taeyong Kim
- & Do Han Kim
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Translocation between PI(4,5)P2-poor and PI(4,5)P2-rich microdomains during store depletion determines STIM1 conformation and Orai1 gating
The Orai1 Ca2+ channel is activated by STIM1 in response to Ca2+ release from the ER. Here Maléth et al.show that Orai1 inactivation occurs by translocation to PI(4,5)P2-rich plasma membrane microdomains, which facilitates recruitment of SARAF, a negative regulator of STIM1 function.
- Jozsef Maléth
- , Seok Choi
- & Malini Ahuja
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Article
| Open AccessTargeting β-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours
MEN1 gene encodes menin, a nuclear scaffold protein that regulates transcription and is often inactivated in pancreatic neuroendocrine tumours (PNETs). Here Jiang et al. show that MEN1-driven PNET development involves activation of β-catenin, and that β-catenin deletion ameliorates the disease.
- Xiuli Jiang
- , Yanan Cao
- & Guang Ning
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Hydrophobic handoff for direct delivery of peroxisome tail-anchored proteins
Delivery and insertion of tail-anchored proteins into peroxisomal membranes requires the chaperone PEX19 and its receptor PEX3. Chen et al.reconstitute this process in a cell-free reaction and show that distinct hydrophobic moieties in PEX19 are required at three separable import steps.
- Yinxiao Chen
- , Laurent Pieuchot
- & Gregory Jedd
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An ecdysone-responsive nuclear receptor regulates circadian rhythms in Drosophila
The mammalian circadian clock is influenced by nuclear receptors such as Rev-Erb. Here Kumar et al. show that ecdysone-induced protein 75 (E75), a fly homologue of Rev-Erb, regulates circadian rhythms in Drosophila, and demonstrate that E75 protects the clock against environmental stressors.
- Shailesh Kumar
- , Dechun Chen
- & Amita Sehgal
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Direct conversion of mouse and human fibroblasts to functional melanocytes by defined factors
Some skin pigment disorders such as vitiligo are caused by the loss of melanocytes, the pigment-producing cells in the skin. Here the authors present an approach to directly convert mouse and human dermal fibroblasts into functional melanocytes.
- Ruifeng Yang
- , Ying Zheng
- & Xiaowei Xu
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BMP signalling regulates the pre-implantation development of extra-embryonic cell lineages in the mouse embryo
BMP signalling is important in early post-implantation embryonic development. Here the authors perform mRNA sequencing of inside and outside cells of pre-implantation mouse embryos and show that BMP signalling is critical for the development of the two extra-embryonic lineages at this early stage.
- Sarah J. L. Graham
- , Krzysztof B. Wicher
- & Magdalena Zernicka-Goetz
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Evidence for zoonotic potential of ovine scrapie prions
Scrapie, a form of prion disease that affects sheep and goats, is believed not to be transmissible to humans. Using transgenic mice expressing human prion protein as a model of cross-species prion transmission, the authors show that ovine scrapie may possess potential to be passed on to humans.
- Hervé Cassard
- , Juan-Maria Torres
- & Olivier Andréoletti
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Article
| Open AccessDirect evidence for BBSome-associated intraflagellar transport reveals distinct properties of native mammalian cilia
Loss of olfactory function is one of the many symptoms of the ciliopathy Bardet–Biedl syndrome. Williams et al. show that Bardet–Biedl proteins are components of intraflagellar transport particles within cilia, and directly visualize their trafficking in native mammalian olfactory neurons.
- Corey L. Williams
- , Jeremy C. McIntyre
- & Jeffrey R. Martens
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Article
| Open AccessControl of membrane gaps by synaptotagmin-Ca2+ measured with a novel membrane distance ruler
Synaptotagmin-1 (syt-1) triggers fast synchronous neurotransmission mediated by fusion of synaptic vesicles with presynaptic membranes. Here Lin et al. use inter-membrane FRET combined with DNA rulers as calibration standards to quantify Ca2+-induced changes in membrane distances mediated by syt-1.
- Chao-Chen Lin
- , Jan Seikowski
- & Peter Jomo Walla
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STAT3 restrains RANK- and TLR4-mediated signalling by suppressing expression of the E2 ubiquitin-conjugating enzyme Ubc13
The transcription factor STAT3 regulates production of inflammatory cytokines by modulating NF-κB signalling. Here the authors show that STAT3 is a transcriptional repressor of the E2 ubiquitin-conjugating enzyme Ubc13, modulating NF-κB by regulating Ubc13 abundance.
- Huiyuan Zhang
- , Hongbo Hu
- & Stephanie S. Watowich
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MinCD cell division proteins form alternating copolymeric cytomotive filaments
MinC, MinD and MinE proteins form part of an oscillatory network that ensures bacteria divide precisely at their midpoints. Ghosal et al.show that MinC and MinD can form membrane-binding copolymers, and propose a mechanism by which these copolymers may regulate cytokinetic ring assembly.
- Debnath Ghosal
- , Daniel Trambaiolo
- & Jan Löwe
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Constitutive and ligand-induced EGFR signalling triggers distinct and mutually exclusive downstream signalling networks
Epidermal growth factor receptor (EGFR) elicits the signalling function after dimerization and activation of its kinase activity and perturbations in this pathway are often found in cancer. Here the authors describe two distinct and mutually exclusive modes of EGFR signalling due to a switch of EGFR-associated proteins with the ligand.
- Sharmistha Chakraborty
- , Li Li
- & Amyn A. Habib
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Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7
The kinase LRRK2 is implicated in Parkinson’s disease progression and is known to be phosphorylated. Chia et al.show that this phosphorylation is mediated by the kinase CK1a, and is required for the recruitment of LRRK2 to Golgi-derived vesicles, suggesting a role for this protein in Golgi maintenance.
- Ruth Chia
- , Sara Haddock
- & Mark R. Cookson
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Article
| Open AccessArteries are formed by vein-derived endothelial tip cells
Sprouting of new blood vessels depends on the migration of endothelial tip cells into surrounding tissue. Here the authors reveal the existence of a distinct migratory signalling circuit that guides endothelial cells from developing veins to the leading tip position in developing arteries.
- Cong Xu
- , Sana S. Hasan
- & Arndt F. Siekmann
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Article
| Open AccessSerotonergic neurons respond to nutrients and regulate the timing of steroid hormone biosynthesis in Drosophila
Steroidal hormones play a major role in the transition from juvenile-to-adult stages of development. Here, Shimada-Niwa and Niwa show that production of one such hormone in the prothoracic gland of Drosophila melanogaster, is regulated by a subset of serotonergic neurons innervating the prothoracic gland.
- Yuko Shimada-Niwa
- & Ryusuke Niwa
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Article
| Open AccessClusterin facilitates stress-induced lipidation of LC3 and autophagosome biogenesis to enhance cancer cell survival
The induction of autophagy under stress conditions such as chemotherapy is a contributing factor towards resistance to anticancer therapy. Here, Zhang et al. identify the molecular chaperone clusterin as an adaptor that facilitates lipidation of LC3 and autophagosome biogenesis.
- Fan Zhang
- , Masafumi Kumano
- & Martin E. Gleave
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The CDC13-STN1-TEN1 complex stimulates Pol α activity by promoting RNA priming and primase-to-polymerase switch
The Cdc13-Stn1-Ten1 (CST) complex recognizes the G-strand of telomeres and functions in telomere protection and replication. Using purified components, the authors show that the Stn1 subunit of the CST complex stimulates RNA priming and the primase-to-polymerase switch by primase-Pol α in fungal and human systems.
- Neal F. Lue
- , Jamie Chan
- & Jerard Hurwitz
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Article
| Open AccessSpartan deficiency causes genomic instability and progeroid phenotypes
Spartan/DVC1 is a translesion synthesis regulator with important roles in cellular DNA damage tolerance. Here, the authors report that Spartan is essential for DNA lesion bypass and that Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes.
- Reeja S. Maskey
- , Myoung Shin Kim
- & Yuichi J. Machida
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Regulation of tyrosine hydroxylase transcription by hnRNP K and DNA secondary structure
Regulation of tyrosine hydroxylase gene (Th) transcription is critical for specifying and maintaining the dopaminergic phenotype. Here the authors show that ribonucleoprotein hnRNP K regulates the Th transcription by binding GC-rich regions of the Thpromoter that are prone to form DNA secondary structures.
- Kasturi Banerjee
- , Meng Wang
- & John W. Cave
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Cell dipole behaviour revealed by ECM sub-cellular geometry
Cells probe and respond to their physical environment by exerting force on their surroundings. Here Mandal et al.grow cells in the same shape and area but on different adhesive patterns to show that they integrate information on extra-cellular matrix geometry at the whole-cell level.
- Kalpana Mandal
- , Irène Wang
- & Martial Balland
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Article
| Open AccessOM14 is a mitochondrial receptor for cytosolic ribosomes that supports co-translational import into mitochondria
Mitochondrial proteins can be imported post-translationally; however, a role for co-translational import has recently provoked renewed interest. Lesnik et al.identify OM14 as a mitochondrial ribosome receptor required for efficient co-translational import of mitochondrial proteins.
- Chen Lesnik
- , Yifat Cohen
- & Yoav Arava
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BIN1/M-Amphiphysin2 induces clustering of phosphoinositides to recruit its downstream partner dynamin
BIN1/M-Amphiphysin2 is a membrane tubulating protein involved in muscle T-tubule biogenesis and whose loss-of-function is associated with centronuclear myopathies. Picas et al.show that BIN1 enhances the recruitment of its binding partner, dynamin, by clustering PtdIns(4,5)P2 in the plasma membrane.
- Laura Picas
- , Julien Viaud
- & Bruno Goud
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Article
| Open AccessCritical role of lysine 134 methylation on histone H2AX for γ-H2AX production and DNA repair
γ-H2AX The Ser139 phosphorylated form of H2AX, γ-H2AX, is generated in response to DNA double-strand breaks and is involved in the repair process. Here, Sone et al.show that H2AX K134 methylation by SUV39H2 is crucial for the production of γ-H2AX, and that loss of methylation correlates with radio- and chemosensitivity.
- Kenbun Sone
- , Lianhua Piao
- & Ryuji Hamamoto
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The internal Cdc20 binding site in BubR1 facilitates both spindle assembly checkpoint signalling and silencing
Kinetochores that fail to form bipolar attachments to the mitotic spindle delay chromosome segregation by BubR1 mediated inhibition of Cdc20. Lischetti et al.show that BubR1 recruits Cdc20 to the kinetochore via a domain that mediates both checkpoint activation and silencing.
- Tiziana Lischetti
- , Gang Zhang
- & Jakob Nilsson
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Article
| Open AccessMitotic catenation is monitored and resolved by a PKCε-regulated pathway
Cells are protected from cell division errors by a pathway that detects mitotic catenation. Here, Brownlow et al.show that protein kinase Cε functions in this pathway to drive decatenation, while delaying silencing of the spindle assembly checkpoint to allow time for catenation resolution.
- Nicola Brownlow
- , Tanya Pike
- & Peter J. Parker
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Review Article |
The role of protein clearance mechanisms in organismal ageing and age-related diseases
Proteins are subject to continuous and complex quality-control mechanisms, which ensure integrity of the proteome. Vilchez et al.review how a demise in these processes, collectively referred to as proteostasis, is linked to organismal ageing and the development of age-associated diseases.
- David Vilchez
- , Isabel Saez
- & Andrew Dillin
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Architecture and dynamic remodelling of the septin cytoskeleton during the cell cycle
In budding yeast, septin filaments adopt an hourglass structure at the bud neck that is remodelled into a double ring. Ong et al.reveal in fine detail the dynamic reorganization of septin filaments within these structures through the cell cycle using platinum-replica electron microscopy.
- Katy Ong
- , Carsten Wloka
- & Erfei Bi
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Article
| Open AccessDynamic SUMO modification regulates mitotic chromosome assembly and cell cycle progression in Caenorhabditis elegans
The ubiquitin-like modifier SUMO is involved in many aspects of the cell cycle, but its dynamics during mitosis are unknown. Here, Pelisch et al.use C. elegans to show that SUMO accumulates on the metaphase plate and is required for proper chromosome alignment, and deconjugation is required to progress through the cell cycle.
- Federico Pelisch
- , Remi Sonneville
- & Ronald T. Hay
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Direct cellular delivery of human proteasomes to delay tau aggregation
Increasing the activity of the proteasome can prevent the accumulation of protein aggregates within the cell. Han et al.show that nanoparticle-mediated delivery of purified proteasomes to cells reduces proteotoxic stress resulting from tau overexpression, and prevents to accumulation of tau aggregates.
- Dong Hoon Han
- , Hee-Kyung Na
- & Min Jae Lee
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Article |
Hepatic miR-378 targets p110α and controls glucose and lipid homeostasis by modulating hepatic insulin signalling
PI3K is a central component of the insulin signalling pathway. Here, the authors reveal that miR-378 expression in the liver changes dynamically in response to fasting or refeeding, and show that miR-378 regulates hepatic insulin signalling by targeting the P110a subunit of PI3K.
- Wei Liu
- , Hongchao Cao
- & Hao Ying
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Article |
Exosomes as Hedgehog carriers in cytoneme-mediated transport and secretion
Long, thin projections of the cell membrane known as cytonemes are required for signalling by the secreted morphogen Hedgehog. Gradilla et al.show that cytonemes carry Hedgehog-associated exovesicles, and that exovesicle formation is required for graded Hedgehog signalling.
- Ana-Citlali Gradilla
- , Esperanza González
- & Isabel Guerrero
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Cryo-electron tomography reveals ciliary defects underlying human RSPH1 primary ciliary dyskinesia
Our current understanding of cilia biology and ciliary diseases is incomplete, in part because cilia are hard to visualize. Here, the authors use cryo-electron tomography to image the structure of human cilia with high resolution and uncover the elusive ciliary defects in Primary Ciliary Dyskinesia patients.
- Jianfeng Lin
- , Weining Yin
- & Daniela Nicastro
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Article |
Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner
The anti-apoptotic protein Mcl-1 and haplo-insufficient tumour suppressor Beclin-1 are deregulated in several cancers. Here the authors show that Mcl-1 and Beclin-1 compete for binding to the deubiquitinase USP9X, resulting in a reciprocal regulation during melanoma progression.
- Mohamed Elgendy
- , Marco Ciro
- & Saverio Minucci
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Somatic transcriptome priming gates lineage-specific differentiation potential of human-induced pluripotent stem cell states
Molecular and functional differences between induced pluripotent stem cells (iPSCs) derived from distinct cell types have been described. Here the authors show, by comparing human iPSCs derived from fibroblasts or cord blood, that the competence in activating developmental genes upon differentiation is influenced by the donor cell of origin.
- Jong-Hee Lee
- , Jung Bok Lee
- & Mickie Bhatia
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Article |
Mus81-Mms4 and Yen1 resolve a novel anaphase bridge formed by noncanonical Holliday junctions
Recombination intermediates must be resolved by mitosis to allow proper chromosome segregation. Here, the authors show that the structure-specific endonucleases Mus81-Msms4 and Yen1 are involved in the resolution of non-canonical Holliday junctions that would otherwise lead to anaphase bridges.
- Jonay García-Luis
- & Félix Machín
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FGF signalling restricts haematopoietic stem cell specification via modulation of the BMP pathway
BMP signalling is required for the emergence of haematopoietic stem cells (HSCs) from the zebrafish dorsal aorta. Here the authors show that FGF signalling negatively regulates HSC emergence by downregulating BMP activity in the zebrafish subaortic mesenchyme and upregulating the expression of BMP antagonists in the somite.
- Claire Pouget
- , Tessa Peterkin
- & Roger Patient
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Article |
A genetic variant of p53 restricts the mucous secretory phenotype by regulating SPDEF and Bcl-2 expression
p53 suppresses the proto-oncogene, Bcl-2, but the mechanism of this regulation is unclear. Here the authors show that p53 regulates bcl-2 mRNA half-life by interacting with its 5′ untranslated region, which has implications on Bcl-2 activity and mucous production in the lung.
- Hitendra S. Chand
- , Gilbert Montano
- & Yohannes Tesfaigzi
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FGF signalling specifies haematopoietic stem cells through its regulation of somitic Notch signalling
In zebrafish embryos, Wnt and Notch signalling have been implicated in the emergence of haematopoietic stem cells during somitogenesis. Here the authors show that FGF signalling via FGFR4 acts downstream of Wnt signalling to regulate the levels of the Notch ligand DeltaC and therefore Notch pathway activity.
- Yoonsung Lee
- , Jennifer E. Manegold
- & David Traver
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Article |
Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex
Microglia colonize germinal regions of the developing cerebral cortex and contribute to the regulation of neurogenesis but the mechanisms that regulate this are not clear. Here the authors show that brain progenitor cells, through the secretion of the chemokine Cxcl12, drive microglia to cluster into the germinal regions of the developing mouse cerebral cortex.
- Benedetta Arnò
- , Francesca Grassivaro
- & Luca Muzio
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