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Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle
Endoplasmic reticulum (ER) stress is observed in diabetes and has been linked to insulin resistance in various tissues. Here, Koh and colleagues show the protein Tribbles 3, which is induced by ER stress and obesity in mice and humans, is an inhibitor of insulin signalling in skeletal muscle.
- Ho-Jin Koh
- , Taro Toyoda
- & Laurie J. Goodyear
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Formin mDia1 senses and generates mechanical forces on actin filaments
Formins are a family of protein complexes that accelerate actin filament nucleation and elongation. Jegou et al.show that the formin mDia1 can generate mechanical tension in actin filaments, while conversely, pulling forces applied by viscous drag increase formin elongation activity.
- Antoine Jégou
- , Marie-France Carlier
- & Guillaume Romet-Lemonne
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R-Spondin 2 signalling mediates susceptibility to fatal infectious diarrhoea
Citrobacter rodentiumis an intestinal pathogen of mice widely used to model enteropathogenicE. coli infection in humans. Using a forward genetic approach, Papapietro and colleagues identify R-Spondin 2 expression and resulting Wnt signalling activation as a major regulator of C. rodentium-induced colitis.
- Olivier Papapietro
- , Sarah Teatero
- & Samantha Gruenheid
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Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway
Clusterin is widely distributed in tissues and body fluids, and is implicated in various physiological processes. In this study the authors investigate the role of hypothalamic clusterin, and find that clusterin regulates energy metabolism and body weight through the lipoprotein receptor LRP2.
- So Young Gil
- , Byung-Soo Youn
- & Min-Seon Kim
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| Open AccessALKBH4-dependent demethylation of actin regulates actomyosin dynamics
The division of a single eukaryotic cell into two requires actomyosin-dependent contraction. Here the authors show that lysine methylation of actin inhibits contractility during cytokinesis by blocking its association with myosin, and this modification is reversed at the contractile ring by the demethylase ALKBH4.
- Ming-Ming Li
- , Anja Nilsen
- & Yun-Gui Yang
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Coordinated activation of the Rac-GAP β2-chimaerin by an atypical proline-rich domain and diacylglycerol
Chimaerins are small GTPase-activating proteins that regulate Rac signalling in response to diacylglycerol. Here the authors discover that activation of β2-chimaerin requires an additional stimulus, in the form of an atypical interaction with the adaptor protein Nck.
- Alvaro Gutierrez-Uzquiza
- , Francheska Colon-Gonzalez
- & Marcelo G. Kazanietz
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Prions disturb post-Golgi trafficking of membrane proteins
Prion protein accumulation in endosomal vesicles has been implicated in the progression of prion diseases. Uchiyama and colleagues infect neuronal cells with prion proteins and find that this delays post-Golgi vesicular trafficking of membrane proteins and impairs insulin signalling.
- Keiji Uchiyama
- , Naomi Muramatsu
- & Suehiro Sakaguchi
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| Open AccessSUMO2/3 modification of cyclin E contributes to the control of replication origin firing
The organized initiation of DNA replication at sites throughout the genome must be carefully choreographed to maintain genome stability. Bonne-Andrea and colleagues show that protein SUMOylation controls the density of origin firing, and identify cyclin E as an important substrate in this context.
- Catherine Bonne-Andrea
- , Malik Kahli
- & Olivier Coux
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| Open AccessSpatial segregation of polarity factors into distinct cortical clusters is required for cell polarity control
Cell polarity is generated and maintained by the spatial accumulation of polarity factors. By imaging fission yeast cells ‘end-on’, the authors show that the polarity factors Tea1 and Tea3 segregate into distinct clusters, and that surprisingly, their segregation is critical for cell polarization.
- James Dodgson
- , Anatole Chessel
- & Rafael E. Carazo-Salas
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| Open AccessPAD4 regulates proliferation of multipotent haematopoietic cells by controlling c-myc expression
Histone citrullination by peptidylarginine deiminase 4 (PAD4) regulates transcription but its physiological role is unclear. Here Nakashima et al. show that PAD4 controls proliferation of multipotent haematopoietic cells by modulating c-myc expression.
- Katsuhiko Nakashima
- , Satoko Arai
- & Toru Miyazaki
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| Open AccessCalfacilitin is a calcium channel modulator essential for initiation of neural plate development
Calcium signalling has been implicated in neural induction in the embryo. The authors identify Calfacilitin as a regulator of CaV1.2 calcium channels, which is required for induction of the pre-neural specifiers Geminin and Sox2 in the early chick embryo.
- Costis Papanayotou
- , Irene De Almeida
- & Claudio D. Stern
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| Open AccessProteolysis of MOB1 by the ubiquitin ligase praja2 attenuates Hippo signalling and supports glioblastoma growth
Tumour suppressors can be inactivated in cancer not only as a result of mutation, but also by proteolytic degradation. Here the authors show that, during glioma development, the accumulation of the ubiquitin ligase praja2 sustains tumour growth by degrading MOB1—a core component of the Hippo pathway.
- Luca Lignitto
- , Antonietta Arcella
- & Antonio Feliciello
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| Open AccessEstablishment of a robust single axis of cell polarity by coupling multiple positive feedback loops
A positive feedback loop which results in localized accumulation of the small GTPase Cdc42 generates cell polarity in budding yeast; however, such loops are inherently susceptible to noise. Here the authors demonstrate how two pathways that mediate Cdc42 recycling work together to ensure the robustness of symmetry breaking.
- Tina Freisinger
- , Ben Klünder
- & Roland Wedlich-Söldner
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Regulation of adipose oestrogen output by mechanical stress
Aberrant production of oestrogens by adipose stromal cells is a driving factor in oestrogen receptor-positive breast cancer. Here the authors discover that oestrogen synthesis in adipose tissue is regulated by mechanical stress, and reveal how this effect is mediated.
- Sagar Ghosh
- , Keith Ashcraft
- & Rong Li
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A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases
Mutations in polyglutamine proteins are implicated in neurodegenerative disorders. Okazawa and colleagues now demonstrate that mutant polyQ proteins interact directly with the ATPase TERA, resulting in reduced DNA double-strand break repair, which is a feature of neurodegenerative diseases.
- Kyota Fujita
- , Yoko Nakamura
- & Hitoshi Okazawa
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| Open AccessDeletion of cavin genes reveals tissue-specific mechanisms for morphogenesis of endothelial caveolae
Cavin proteins are key components of mammalian caveolae and are expressed from four genes in a tissue-specific manner. Gram Hansen et al. demonstrate that caveolae in the endothelia of different tissues are remarkably heterogeneous, and reveal a role for cavin 2 in determining the apparent size of cavin complexes.
- Carsten Gram Hansen
- , Elena Shvets
- & Benjamin James Nichols
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Ultraviolet-B-mediated induction of protein–protein interactions in mammalian cells
Light-sensitive proteins are useful tools to control protein localization and gene expression, but are currently limited to excitation with red or blue light. Here Crefcoeur et al. present a novel optogenetic system to induce protein–protein interactions with ultraviolet-B light that does not require exogenous chromophores.
- Remco P. Crefcoeur
- , Ruohe Yin
- & Thanos D. Halazonetis
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Regulation of asymmetric cell division and polarity by Scribble is not required for humoral immunity
B cells are thought to divide asymmetrically to generate distinct lineages required for adaptive immunity. Hawkins et al. find that surprisingly, mice lacking components of a complex required for asymmetric cell division display normal responses to vaccination and viral infection.
- Edwin D. Hawkins
- , Jane Oliaro
- & Sarah M. Russell
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SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress
Centrosome duplication during cell division is controlled by the polo-like kinase PLK4. Nakamura et al. reveal how stress-activated protein kinase and the tumour suppressor p53 act together to regulate PLK4, and show that their combined loss in cancer cells leads to the appearance of supernumerary centrosomes.
- Takanori Nakamura
- , Haruo Saito
- & Mutsuhiro Takekawa
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Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation
Tumour cells may undergo a dramatic metabolic shift in which glycolysis is favoured despite the presence of oxygen. By solving its crystal structure, Hitosugi et al. reveal how phosphorylation of the enzyme phosphoglycerate mutase 1 regulates glycolytic flux in cancer cells.
- Taro Hitosugi
- , Lu Zhou
- & Jing Chen
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| Open AccessOptimization of stress response through the nuclear receptor-mediated cortisol signalling network
Stress causes cortisol release and this is associated with the development of pathophysiology. Plant and colleagues use a computational model to reproduce the interaction of cortisol with its two nuclear receptors, and reveal how feed-forward and feed-back loops coordinate adaptation to repeated stress.
- Alexey Kolodkin
- , Nilgun Sahin
- & Nick Plant
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Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis
Cancer-associated fibroblasts promote tumour growth and metastasis by secreting signalling molecules. Jung and colleagues show that prostate cancer cells secrete CXC chemokine ligand 16, which recruits mesenchymal stem cells and converts them into cancer-associated fibroblasts.
- Younghun Jung
- , Jin Koo Kim
- & Russell S. Taichman
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Non-hyperpolarizing GABAB receptor activation regulates neuronal migration and neurite growth and specification by cAMP/LKB1
Early neural development is regulated by the neurotransmitter GABA acting through ionotropic GABAA receptors; however, the function of metabotropic GABAB receptors in this context is less clear. Here the authors show that GABABreceptors promote neuronal migration and maturation by activating cAMP signalling.
- Guillaume Bony
- , Joanna Szczurkowska
- & Laura Cancedda
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Competing signals drive telencephalon diversity
The brains of rock- and sand-dwelling Lake Malawi cichlid fishes differ in telencephalon partitioning. Sylvester et al. show that these differences can be attributed to divergence in Hedgehog and Wingless signalling during development.
- J B. Sylvester
- , C A. Rich
- & J T. Streelman
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Dual role of myosin II during Drosophila imaginal disc metamorphosis
The motor protein myosin II is implicated in three-dimensional organ development. In this study, the authors apply live imaging techniques to describe the dynamics of the developing Drosophilawing and the involvement of myosin II in this process.
- Silvia Aldaz
- , Luis M. Escudero
- & Matthew Freeman
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| Open AccessmiR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit
Brown fat can dissipate energy as heat and has an important role in energy homoeostasis of rodents and possibly humans. Chenet al. show that microRNA 155 regulates the differentiation of brown adipocytes as well as the 'browning' of white fat cells in mice.
- Yong Chen
- , Franziska Siegel
- & Alexander Pfeifer
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| Open AccessThe four-transmembrane protein IP39 of Euglena forms strands by a trimeric unit repeat
IP39 is an abundant protozoan protein known to form highly-ordered striations in Euglena gracilis’ plasma membrane. Here, Suzuki et al. determine its three-dimensional structure by electron crystallography revealing that IP39 polymerises to form trimeric longitudinal units arranged in a molecular strand of antiparallel double-rows.
- Hiroshi Suzuki
- , Yasuyuki Ito
- & Sachiko Tsukita
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Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics
Vascular permeability is increased by inflammation and in disorders such as acute respiratory distress syndrome. Mammoto et al. show that lung vascular permeability is controlled by the stiffness of the extracellular matrix and identify lysyl oxidase as a regulator of vascular leakage in pulmonary oedema in mice.
- Akiko Mammoto
- , Tadanori Mammoto
- & Donald E. Ingber
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Dynamin−SNARE interactions control trans-SNARE formation in intracellular membrane fusion
Dynamin promotes membrane fission by constricting the neck of invaginating membranes; however, it was recently shown that dynamin also regulates membrane fusion. Here the authors show that this fusogenic activity is mediated by interaction with the Qa SNARE, thereby promoting trans-SNARE formation.
- Kannan Alpadi
- , Aditya Kulkarni
- & Christopher Peters
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| Open AccessMechanical unzipping and rezipping of a single SNARE complex reveals hysteresis as a force-generating mechanism
Interactions between (SNARE) proteins on vesicle and target membranes provide the force necessary to drive membrane fusion. By applying piconewton forces to single SNARE complexes, the authors identify a partially assembled intermediate state that reveals how force is generated in a consistent direction.
- Duyoung Min
- , Kipom Kim
- & Tae-Young Yoon
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| Open AccessMutually exclusive regulation of T cell survival by IL-7R and antigen receptor-induced signals
Before antigen exposure, T cell survival is dependent on signalling stimulated by IL-7. Koenen et al. show that upon encountering specific antigen, T cell receptor signalling initiates a different set of survival pathways, which actively suppress those that sustain naive T cells.
- Paul Koenen
- , Susanne Heinzel
- & Philip D. Hodgkin
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| Open AccessAraf kinase antagonizes Nodal-Smad2 activity in mesendoderm development by directly phosphorylating the Smad2 linker region
TGF-β signalling through SMAD transcription factors has been implicated in embryonic mesendoderm development. Liu and colleagues reveal that the Ras-regulated kinase Raf prevents excessive mesendoderm formation by phosphorylating and promoting the degradation of SMAD2.
- Xingfeng Liu
- , Cong Xiong
- & Anming Meng
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Calcium-dependent permeabilization of erythrocytes by a perforin-like protein during egress of malaria parasites
Malaria parasites exit erythrocytes by triggering permeabilization and rupture of the host plasma membrane. Here, the authors identify a perforin-like protein that is secreted by the parasite in a calcium-dependent manner and mediates permeabilization through its insertion into the host membrane.
- Swati Garg
- , Shalini Agarwal
- & Shailja Singh
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Rewiring of human lung cell lineage and mitotic networks in lung adenocarcinomas
Directly comparing patterns of gene expression in matched normal and cancerous tissues provides a powerful tool to identify drivers of tumour progression. Here the authors discover genes that are recruited into mitotic signalling networks in lung adenocarcinoma.
- Il-Jin Kim
- , David Quigley
- & Allan Balmain
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| Open AccessAssociation between Gαi2 and ELMO1/Dock180 connects chemokine signalling with Rac activation and metastasis
Chemokines promote breast cancer metastasis by stimulating re-organization of the actin cytoskeleton. Li et al. identify the human engulfment and cell motility protein ELMO1 as an intermediary between chemokine-dependent Gαi2 signalling and small GTPase signalling mediated by Rac.
- Hongyan Li
- , Lei Yang
- & Ning Zhang
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Regulation of NF-κB signalling by the mono-ADP-ribosyltransferase ARTD10
Mono-ADP-ribosylation is a recently discovered post-translational modification whose function remains unclear. Verheugd et al. show that the mono-ADP-ribosyltransferase ARTD10 inhibits NF-κB activation by preventing the poly-ubiquitination of NEMO, suggesting a functional link between these two modifications.
- Patricia Verheugd
- , Alexandra H. Forst
- & Bernhard Lüscher
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| Open AccessProstaglandin E2 promotes Th1 differentiation via synergistic amplification of IL-12 signalling by cAMP and PI3-kinase
Activation of cAMP signalling by prostaglandin E2 (PGE2) has long been thought to suppress Tcell receptor activation and Th1 cell differentiation. Yao et al. reveal that dual stimulation of both cAMP and PI 3-kinase pathways by PGE2 synergistically promotes Th1 differentiation by amplifying IL-12 and IFN-γsignalling.
- Chengcan Yao
- , Takako Hirata
- & Shuh Narumiya
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Mitotic spindle orientation predicts outer radial glial cell generation in human neocortex
Human neocortex expansion is partly due to neuronal production by outer radial glial cells. In the developing human cortex, LaMonica et al. find that horizontal divisions of ventricular radial glial cells produce outer radial glial cells displaying cell-intrinsic regulation of mitosis and spindle orientation.
- Bridget E. LaMonica
- , Jan H. Lui
- & Arnold R. Kriegstein
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| Open AccessA role for Piezo2 in EPAC1-dependent mechanical allodynia
Mechanical allodynia describes the process whereby innocuous stimuli is perceived as being noxious and is a common symptom of neuropathic pain. Using mice deficient in the cAMP sensor Epac1, the authors in this study find that Epac1 regulates mechanical allodynia by sensitizing the mechanotransducer Piezo2.
- N Eijkelkamp
- , J.E. Linley
- & J.N. Wood
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Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81
The skeletal muscle has a remarkable capacity to regenerate after injury. Here Charrin et al. reveal that restoration of muscle architecture after injury requires a tight control of muscle cell fusion by the tetraspanin proteins CD9 and CD81 through their interaction with the cell surface protein CD9P-1.
- Stéphanie Charrin
- , Mathilde Latil
- & Eric Rubinstein
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FBXW7α attenuates inflammatory signalling by downregulating C/EBPδ and its target gene Tlr4
The innate immune sensor Toll-like receptor 4 controls inflammatory gene expression. Here the authors identify a network of positive and negative feedback loops involving the transcription factor C/EBPd and ubiquitin ligase substrate adaptor FBXW7a that regulate TLR4 levels and inflammatory signalling.
- Kuppusamy Balamurugan
- , Shikha Sharan
- & Esta Sterneck
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| Open AccessVE-PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation
Vascular endothelial growth factor is implicated in blood vessel development. In zebrafish, Hayashi et al. find that blood vessel development is dependent on the suppression of vascular endothelial growth factor by the phosphatase VE-PTP, which is recruited by activation of the angiopoietin receptor Tie2.
- Makoto Hayashi
- , Arindam Majumdar
- & Lena Claesson-Welsh
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Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK
PEA-15 is a scaffold protein that regulates the localization and phosphorylation of the MAP kinase ERK2. By solving the structure of the PEA-15/ERK2 complex, the authors show that PEA-15 restrains ERK2 in a spring-loaded, activated form.
- Peter D. Mace
- , Yann Wallez
- & Stefan J. Riedl
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Regulation of protein glycosylation and sorting by the Golgi matrix proteins GRASP55/65
GRASP proteins are thought to play a role in maintaining the stacked structure of the Golgi complex. Xiang et al. discover that depletion of GRASPs accelerates Golgi traffic, but reduces the complexity of Golgi protein glycosylation.
- Yi Xiang
- , Xiaoyan Zhang
- & Yanzhuang Wang
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Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated β1/β2-integrin trafficking
Klf5 is a transcription factor that regulates self-renewal of pluripotent stem cells. Here the authors test the function of Klf5 in somatic stem cells, and discover that it controls stem cell homing and adhesion by regulating endocytosis of beta integrins.
- E. Taniguchi Ishikawa
- , K. H. Chang
- & J. A. Cancelas
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Ets2-dependent trophoblast signalling is required for gastrulation progression after primitive streak initiation
The transcription factor Ets2 is expressed in the extraembryonic ectoderm tropoblast during gastrulation. Here, the authors use Ets2 knock-out mice to show that Ets2 signalling is required for gastrulation, primitive streak elongation and development and the mesoderm epithelial-to-mesenchymal transition.
- Christiana Polydorou
- & Pantelis Georgiades
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| Open AccessRnd3 coordinates early steps of cortical neurogenesis through actin-dependent and -independent mechanisms
The atypical RhoGTPase Rnd3 is implicated in the regulation of neuronal migration in the embryonic cerebral cortex. Using gene silencing techniques, Pacary and colleagues find that Rnd3 is also involved in earlier stages of neurogenesis, by modulating actin filament polymerization and cyclin D1 translation.
- Emilie Pacary
- , Roberta Azzarelli
- & François Guillemot
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Probing transcription factor diffusion dynamics in the living mammalian embryo with photoactivatable fluorescence correlation spectroscopy
Transcription factor diffusion along DNA regulates many fundamental cellular and developmental processes. Kaur et al. combine photoactivation and fluorescence correlation spectroscopy to investigate transcription factor diffusion in mouse embryos and show that diffusion kinetics change during cell differentiation.
- Gurpreet Kaur
- , Mauro W. Costa
- & Nicolas Plachta
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Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes
Crystallins are structural proteins that are expressed on the outside of the lens of the eye. Valapala and colleagues find that specific crystallins in retinal astrocytes regulate V-ATPase activity and endolysosomal acidification, to facilitate optimal Notch signalling during retinal development.
- Mallika Valapala
- , Stacey Hose
- & Debasish Sinha
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