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| Open AccessControl of synaptic vesicle endocytosis by an extracellular signalling molecule
Synaptic vesicle endocytosis is required for neurotransmission at nerve terminals. Smillie et al. show that brain-derived neurotrophic factor inhibits a specific type of synaptic vesicle endocytosis, which reverses the depression of neurotransmission observed during high-intensity stimulation.
- Karen J. Smillie
- , Jonathan Pawson
- & Michael A. Cousin
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Modulation of β-catenin function maintains mouse epiblast stem cell and human embryonic stem cell self-renewal
Wnt/β-catenin signalling can regulate both self-renewal and differentiation of pluripotent stem cells. Here Kim et al.show that transcriptional regulation by nuclear β-catenin induces the differentiation of mouse epiblast stem cells and human embryonic stem cells, whereas cytoplasmic β-catenin supports their self-renewal.
- Hoon Kim
- , Jun Wu
- & Qi-Long Ying
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MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling
The protein MG53 is known to inhibit myogenesis. Here, Ko et al. show that MG53 is an E3 ubiquitin ligase that mediates degradation of insulin receptor substrate 1 in skeletal muscle, thereby regulating myogenesis and insulin sensitivity in vitro and in vivo.
- Jae-Sung Yi
- , Jun Sub Park
- & Young-Gyu Ko
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Article
| Open AccessATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy
The protein ATG5 is known to be involved in the formation of autophagosomes. Here, Maskey et al. identify a new role of ATG5 in response to drug-induced DNA damage whereby ATG5 translocates to the nucleus, leading to chromosome misalignment and mitotic catastrophe.
- Dipak Maskey
- , Shida Yousefi
- & Hans-Uwe Simon
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Bcl-wav and the mitochondrial calcium uniporter drive gastrula morphogenesis in zebrafish
Ca2+ is an intracellular messenger that has a critical role in zebrafish development. Here Prudent et al. show that during gastrulation, the newly identified Bcl-2 homologue, Bcl-wav and the mitochondrial calcium uniporter regulate cell migration by controlling mitochondrial Ca2+storage.
- Julien Prudent
- , Nikolay Popgeorgiev
- & Germain Gillet
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| Open AccessOverexpression of Atg5 in mice activates autophagy and extends lifespan
Changes in autophagy have been shown to modulate lifespan in lower organisms. Here, Pyo et al.show that mice globally overexpressing the autophagy protein Atg5 live longer and are leaner than normal mice, providing the first evidence that increased autophagy extends lifespan in mammals.
- Jong-Ok Pyo
- , Seung-Min Yoo
- & Yong-Keun Jung
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The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans
The mammalian protein TFEB is a key regulator of autophagy, a cellular process implicated in organismal ageing. Here, Lapierre et al. show that the TFEB orthologue HLH-30 is required for lifespan extension in six different long-lived Caenorhabditis elegansstrains.
- Louis R. Lapierre
- , C. Daniel De Magalhaes Filho
- & Malene Hansen
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| Open AccessTubular endocytosis drives remodelling of the apical surface during epithelial morphogenesis in Drosophila
During epithelial morphogenesis in Drosophila, the villous apical cell surface is flattened. Fabrowski et al. show that this flattening depends on a dramatic increase in endocytosis associated with the formation of tubular invaginations, revealing a role for membrane trafficking in morphological remodelling.
- Piotr Fabrowski
- , Aleksandar S. Necakov
- & Stefano De Renzis
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The unusual dynamics of parasite actin result from isodesmic polymerization
Actin normally polymerizes into filaments in a cooperative manner, with nucleation and elongation phases. Skillman et al. show that actin from the protozoan parasite Toxoplasma gondiipolymerizes in an isodesmic manner, without any evidence of nucleation, resulting in filaments that are very short and unstable.
- Kristen M. Skillman
- , Christopher I. Ma
- & L. David Sibley
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A systematic analysis of the PARP protein family identifies new functions critical for cell physiology
The poly(ADP-ribose) polymerase (PARP) family includes 17 proteins in humans, many of which have no known function. Vyas et al.systematically characterize the localization and function of each human PARP and identify PARP14 as a regulator of focal adhesions.
- Sejal Vyas
- , Melissa Chesarone-Cataldo
- & Paul Chang
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| Open AccessPrelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion
Mutations in the metalloproteinase Zmpste24 preclude prelamin A processing and cause premature ageing. Here, de la Rosaet al.create mosaic Zmpste24 mice, revealing that cell-extrinsic effects are essential for accelerated ageing caused by prelamin A accumulation and that prelamin A reduces invasiveness of cancer cells.
- Jorge de la Rosa
- , José M.P. Freije
- & Carlos López-Otín
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| Open AccessVisualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities
Poly-ADP-ribosylation is a post-translational modification that is countered by poly(ADP-ribose) glycohydrolases (PARGs). In this study, the authors present the crystal structure of poly(ADP-ribose) glycohydrolase (PARGs) in complex with a poly(ADP-ribose) substrate, and reveal that poly(ADP-ribose) glycohydrolase (PARGs) enzymes act predominantly as exo- rather than as endo-glycohydrolases.
- Eva Barkauskaite
- , Amy Brassington
- & David Leys
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Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart
Damaged mitochondria are removed from cells through a process called mitophagy. Here, Hoshino et al. show that the cytosolic fraction of the protein p53 inhibits mitophagy by sequestering the mitophagy regulator Parkin, leading to impaired mitochondrial integrity and cardiac function in aged or damaged mouse hearts.
- Atsushi Hoshino
- , Yuichiro Mita
- & Satoaki Matoba
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Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system
Endosomal sorting is regulated by phosphatidylinositol-3-phosphate and anomalies in this process are implicated in Alzheimer’s disease. Here the authors show that deficiency of phosphatidylinositol-3-phosphate in vitroenhances the pathological trafficking and processing of amyloid precursor protein.
- Etienne Morel
- , Zeina Chamoun
- & Gilbert Di Paolo
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Article
| Open AccessAngiomotin prevents pluripotent lineage differentiation in mouse embryos via Hippo pathway-dependent and -independent mechanisms
Angiomotins retain the transcription co-activator YAP in the cytoplasm and thereby regulate the Hippo pathway in mammalian cultured cells. Here Leung and Zernicka-Goetz show that Angiomotin family members prevent the differentiation of inner cell mass cells in the mouse blastocyst, via both Hippo pathway-dependent and -independent mechanisms.
- Chuen Yan Leung
- & Magdalena Zernicka-Goetz
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Involvement of Bag6 and the TRC pathway in proteasome assembly
The 26S proteasome comprises over 33 different subunits that must be correctly assembled by dedicated chaperones for efficient protein degradation. Here the authors find that general chaperone proteins are also vital for proper proteasome assembly.
- Takashi Akahane
- , Kazutaka Sahara
- & Shigeo Murata
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Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells
Reductive glutamine metabolism supports cell proliferation under stress conditions such as hypoxia. Here Fendtet al.report that the ratio between the two metabolites α-ketoglutarate and citrate determines whether glutamine is metabolized oxidatively or reductively.
- Sarah-Maria Fendt
- , Eric L. Bell
- & Gregory Stephanopoulos
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Synthetic polyamines promote rapid lamellipodial growth by regulating actin dynamics
While small molecules that destabilize actin filaments are readily available, artificially stimulating actin polymerization in cells typically involves genetic manipulation. Here, the authors design cell-permeable branched polyamines that promote lamellipodium formation by stimulating actin polymerization.
- Iliana Nedeva
- , Girish Koripelly
- & Daniel Riveline
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Identification of ROCK1 kinase as a critical regulator of Beclin1-mediated autophagy during metabolic stress
The kinase ROCK1 has been implicated in apoptosis and other cellular functions. Here Gurkar et al. show that ROCK1 phosphorylates the autophagy regulator Beclin1, which activates autophagy by disrupting the association between Beclin-1 and Bcl-2.
- Aditi U. Gurkar
- , Kiki Chu
- & Sam W. Lee
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The p53–PUMA axis suppresses iPSC generation
Inhibition of the p53–p21 axis increases reprogramming efficiency of somatic cells into induced pluripotent stem cells (iPSCs). Here the authors show that depletion of the pro-apoptotic factor PUMA, acting downstream of p53, increases reprogramming efficiency, providing new insights into the roles of p53 in reprogramming.
- Yanxin Li
- , Haizhong Feng
- & Tao Cheng
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SNAP-25 regulates spine formation through postsynaptic binding to p140Cap
The SNARE protein family member, SNAP-25, is implicated in modulating synaptic plasticity. Tomasoni et al. show that SNAP-25 recruits the protein p140Cap in order to regulate the density, morphology and functionality of dendritic spines.
- Romana Tomasoni
- , Daniele Repetto
- & Michela Matteoli
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| Open AccessHace1 controls ROS generation of vertebrate Rac1-dependent NADPH oxidase complexes
HACE1 is an E3 ligase that promotes degradation of the GTPase Rac1. Here Daugaard et al. show that HACE1 inhibits the activity of Rac1-dependent NADPH oxidase complexes, which reduces the production of cellular reactive oxygen species and cell cycle progression.
- Mads Daugaard
- , Roberto Nitsch
- & Poul H. Sorensen
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Autonomous vascular networks synchronize GABA neuron migration in the embryonic forebrain
The simultaneous activity of chemorepulsive and chemoattractive gradients is implicated in gamma-aminobutyric acid neuron migration during embryonic development. Won et al.show that preformed vascular networks provide these repulsive and attractive gradients to GABAergic neurons as they migrate through the telencephalon.
- Chungkil Won
- , Zhicheng Lin
- & Anju Vasudevan
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Visualization of caspase-3-like activity in cells using a genetically encoded fluorescent biosensor activated by protein cleavage
Proteases of the caspase family are important regulators of apoptosis. Here, Zhang et al. present a genetically encoded protein biosensor that fluoresces if cleaved by caspase-3-like proteases, allowing real-time measurements of apoptosis in cells.
- Jiao Zhang
- , Xin Wang
- & Binghui Li
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Landscape of the mitochondrial Hsp90 metabolome in tumours
Tumour cells utilize a pool of the molecular chaperone heat shock protein 90 to ensure correct protein folding in mitochondria. Here, the authors demonstrate that mitochondrial heat shock protein 90 regulates the folding of a subunit of the electron transport chain and that this can contribute to tumorigenesis.
- Young Chan Chae
- , Alessia Angelin
- & Dario C. Altieri
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The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells
Intraepithelial lymphocytes (IELs) defend against pathogens in the gut, and their differentiation depends on both diet and microbiota-derived factors. Nakajima et al. show that signalling through the aryl hydrocarbon receptor nuclear translocator and STAT3 is required for the development of a subset of IELs.
- Kohei Nakajima
- , Yoichi Maekawa
- & Koji Yasutomo
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Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma
Impairments in cerebral folate transport are implicated in childhood-onset neurodegeneration. Grapp et al. show that folate receptors in the choroid plexus mediate folate transport by delivering folate receptor-containing exosomes into the brain parenchyma.
- Marcel Grapp
- , Arne Wrede
- & Robert Steinfeld
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Spatiotemporally controlled induction of autophagy-mediated lysosome turnover
Lysosomes are the major degradative compartments within cells, but little is known about cellular mechanisms that control lysosome quality. Here Hung et al.show that lysosomes damaged by light-induced activation of a photosensitizer are selectively ubiquitinated and subsequently eliminated by autophagy.
- Yu-Hsien Hung
- , Lily Man-Wen Chen
- & Wei Yuan Yang
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Caesium accumulation in yeast and plants is selectively repressed by loss of the SNARE Sec22p/SEC22
The active uptake of radiocaesium by plants via potassium transport systems results in contamination of food supplies. Here, the authors show that loss of the v-SNARE protein Sec22p/SEC22 specifically reduces the accumulation of Cs+in yeast and plants by repressing its deposition to vacuoles.
- Stephan Dräxl
- , Johannes Müller
- & Anton R. Schäffner
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Kindlin-1 regulates mitotic spindle formation by interacting with integrins and Plk-1
Kindlin-1 regulates integrin activation at cell adhesions. Here Patel et al.report that Kindlin-1 also localizes to centrosomes where it controls the formation of mitotic spindles in a manner that requires integrin activation and Kindlin-1 phosphorylation by the mitotic kinase Plk-1.
- Hitesh Patel
- , Judith Zich
- & Valerie G. Brunton
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| Open Accessα-Tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors
De novoneurogenesis occurs within the adult hypothalamus, suggesting the existence of a local neural stem cell niche. Here, the authors show that α-tanycytes lining the third ventricle are self-renewing multipotent neural stem cells, whose proliferation is dependent upon local FGF signalling.
- S.C. Robins
- , I. Stewart
- & M. Placzek
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FAK-heterozygous mice display enhanced tumour angiogenesis
Focal adhesion kinase (FAK) regulates angiogenesis and FAK inhibitors are currently developed as anticancer drugs. Here Kostourou and colleagues show that genetic FAK heterozygosity or low doses of a pharmacological FAK inhibitor unexpectedly increase angiogenesis and tumour growth in vitro and in vivo.
- Vassiliki Kostourou
- , Tanguy Lechertier
- & Kairbaan Hodivala-Dilke
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PHF20 regulates NF-κB signalling by disrupting recruitment of PP2A to p65
The protein PHF20 is expressed in various cancers, but little is known about its cellular function. Here, Zhang and colleagues show that PHF20 regulates NF-κB signalling by inhibiting the interaction between its subunit p65 and the phosphatase PP2A, thereby maintaining NF-κB in an active state in the nucleus.
- Tiejun Zhang
- , Kyeong Ah Park
- & Gang Min Hur
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Antagonism between binding site affinity and conformational dynamics tunes alternative cis-interactions within Shp2
Competition between inter- and intra-molecular interactions is a commonly observed property of modular signalling proteins. Here, the authors show that in the phosphatase Shp2, this balance is maintained by a trade-off between binding site affinities and conformational stability.
- Jie Sun
- , Shaoying Lu
- & Yingxiao Wang
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Article
| Open AccessRab6a releases LIS1 from a dynein idling complex and activates dynein for retrograde movement
LIS1 has been shown to act as a protein ‘clutch’, which binds to dynein motor proteins and prevents microtubule detachment without affecting their ATPase activity; this causes dynein to stall. Here the authors show that the GTPase Rab6a releases LIS1 from dynein, thus reactivating the motor.
- Masami Yamada
- , Kanako Kumamoto
- & Shinji Hirotsune
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Article
| Open AccessMitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals
Calcium uptake by the mitochondrial calcium uniporter is implicated in excitotoxicity. This study shows that the uniporter gene product mediates mitochondrial calcium uptake and depolarisation in neurons during excitotoxicity, and is transcriptionally repressed by neuroprotective nuclear calcium signals.
- Jing Qiu
- , Yan-Wei Tan
- & Giles E. Hardingham
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Article
| Open AccessBDNF–TrkB signaling in striatopallidal neurons controls inhibition of locomotor behavior
The neurotrophic factor BDNF is implicated in striatal cell long-term survival. Besusso et al. selectively delete BDNF receptors in the striatal circuitry of mice and find that this leads to hyperlocomotion, which is associated with dopamine receptor-dependent increases in specific kinases.
- Dario Besusso
- , Mirjam Geibel
- & Liliana Minichiello
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Article
| Open AccessMechanism of microtubule array expansion in the cytokinetic phragmoplast
Plant cell division is driven by the expansion of the phragmoplast, a characteristic structure that forms in the middle of the plant cell during cytokinesis. Murata et al. use genetic and cell imaging approaches to clarify the microtubule behaviour that leads to phragmoplast expansion.
- Takashi Murata
- , Toshio Sano
- & Mitsuyasu Hasebe
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Myosin Vb controls biogenesis of post-Golgi Rab10 carriers during axon development
Polarized membrane addition during axon development requires post-Golgi Rab10 carriers, whose biogenesis mechanisms remain unknown. This work shows that specific interaction between Rab10 and MYO5B controls formation of the Rab10 carriers, and this process is essential for neuronal polarization.
- Yang Liu
- , Xiao-Hui Xu
- & Zhen-Ge Luo
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Short-time movement of E. coli chromosomal loci depends on coordinate and subcellular localization
The spatial and temporal organization of bacterial chromosomes is important for many cellular functions. Using high-precision measurements of fluorescently labelled chromosomal loci, Javer et al.demonstrate variation in the dynamics of different chromosomal sites, which may either be due to differential organization of the chromosome or spatial variation in molecular noise.
- Avelino Javer
- , Zhicheng Long
- & Marco Cosentino Lagomarsino
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αTAT1 is the major α-tubulin acetyltransferase in mice
Acetylation of tubulin is proposed to be an important mechanism for the regulation of microtubule stability and diversity. Kalebic et al. generate mice lacking α-tubulin acetyltransferase activity, and reveal that an apparent absence of detectable tubulin acetylation is associated with impaired sperm motility.
- Nereo Kalebic
- , Simona Sorrentino
- & Paul A. Heppenstall
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Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice
Aberrant caspase signalling is implicated in Alzheimer’s disease. Pozueta et al.study a mouse model of Alzheimer’s disease that is deficient in caspase-2 and find that surprisingly, these mice don’t display impaired cognitive function, or the reduced dendritic spine density normally associated with the disease.
- Julio Pozueta
- , Roger Lefort
- & Michael Shelanski
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Article
| Open AccessThe orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms
The murine G protein-coupled receptor 83 (Gpr83) is expressed widely in the brain, but its physiological role is largely unknown. Here Müller et al.show that Gpr83 regulates systemic energy metabolism in part by modulating ghrelin signalling in the arcuate nucleus of the hypothalamus.
- Timo D. Müller
- , Anne Müller
- & Matthias H. Tschöp
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Article
| Open AccessLck tyrosine kinase mediates β1-integrin signalling to regulate Schwann cell migration and myelination
Schwan cells ensheath and insulate axons, enabling efficient transmission of action potentials. Ness and colleagues study the role of the kinase Lck in Schwan cells, and find that Lck signalling regulates cell migration, axonal sorting and myelin thickness.
- Jennifer K. Ness
- , Kristin M. Snyder
- & Nikos Tapinos
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Involvement of the Wnt/β-catenin pathway in neurectoderm architecture in Platynereis dumerilii
The Wnt/β-catenin pathway has important roles during neurogenesis in bilaterian animals. The authors show that this pathway regulates the transition from proliferating neural progenitors to differentiating neurons in the annelid Platynereis dumerilii, suggesting a conserved role in the last common bilaterian ancestor.
- Adrien Demilly
- , Patrick Steinmetz
- & Michel Vervoort
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Article
| Open AccessAurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis
Geminin blocks the inappropriate assembly of pre-replication complexes on DNA, and this activity is inhibited in G1 by its proteasomal degradation. Tsunematsu et al.demonstrate that geminin is stabilized during mitosis due to its phosphorylation by the mitotic kinase Aurora-A.
- Takaaki Tsunematsu
- , Yoshihiro Takihara
- & Yasusei Kudo
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Article
| Open AccessPI 3-kinase-dependent phosphorylation of Plk1–Ser99 promotes association with 14-3-3γ and is required for metaphase–anaphase transition
Polo-like kinase 1 (Plk1) controls the transition between metaphase and anaphase during mitosis. Kasahara et al.show that Plk1 activity is regulated by phosphatidylinositide 3-kinase signalling through phosphorylation at a previously uncharacterized site.
- Kousuke Kasahara
- , Hidemasa Goto
- & Masaki Inagaki
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Article
| Open AccessDll1 maintains quiescence of adult neural stem cells and segregates asymmetrically during mitosis
Neural stem cells in the adult brain maintain their pool size while producing new neurons. Kawaguchi et al.show that, during neural stem cell mitosis in the adult mouse subventricular zone, the Notch ligand Dll1 is asymmetrically segregated to one daughter cell, which undergoes differentiation.
- Daichi Kawaguchi
- , Shohei Furutachi
- & Yukiko Gotoh
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Distinct pathways mediate axon degeneration during apoptosis and axon-specific pruning
Recent studies suggest that there is an overlap between neuronal apoptosis and axon-specific degeneration. Cusack and colleagues show that the caspase-dependent pathways mediating axon degeneration during apoptosis are distinct from those mediating localized axon pruning.
- Corey L. Cusack
- , Vijay Swahari
- & Mohanish Deshmukh
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