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Lkb1 regulates granule cell migration and cortical folding of the cerebellar cortex.
Ryan KE, Kim PS, Fleming JT, Brignola E, Cheng FY, Litingtung Y, Chiang C
(2017) Dev Biol 432: 165-177
MeSH Terms: Animals, Cell Differentiation, Cell Division, Cell Movement, Cerebellar Cortex, Cytoplasmic Granules, Hedgehog Proteins, Mice, Nerve Tissue Proteins, Neurons, Organogenesis, Protein-Serine-Threonine Kinases, Signal Transduction
Show Abstract · Added April 10, 2019
Cerebellar growth and foliation require the Hedgehog-driven proliferation of granule cell precursors (GCPs) in the external granule layer (EGL). However, that increased or extended GCP proliferation generally does not elicit ectopic folds suggests that additional determinants control cortical expansion and foliation during cerebellar development. Here, we find that genetic loss of the serine-threonine kinase Liver Kinase B1 (Lkb1) in GCPs increased cerebellar cortical size and foliation independent of changes in proliferation or Hedgehog signaling. This finding is unexpected given that Lkb1 has previously shown to be critical for Hedgehog pathway activation in cultured cells. Consistent with unchanged proliferation rate of GCPs, the cortical expansion of Lkb1 mutants is accompanied by thinning of the EGL. The plane of cell division, which has been implicated in diverse processes from epithelial surface expansions to gyrification of the human cortex, remains unchanged in the mutants when compared to wild-type controls. However, we find that Lkb1 mutants display delayed radial migration of post-mitotic GCPs that coincides with increased cortical size, suggesting that aberrant cell migration may contribute to the cortical expansion and increase foliation. Taken together, our results reveal an important role for Lkb1 in regulating cerebellar cortical size and foliation in a Hedgehog-independent manner.
Copyright © 2017 Elsevier Inc. All rights reserved.
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MeSH Terms
An amyotrophic lateral sclerosis-linked mutation in GLE1 alters the cellular pool of human Gle1 functional isoforms.
Aditi , Glass L, Dawson TR, Wente SR
(2016) Adv Biol Regul 62: 25-36
MeSH Terms: Amyotrophic Lateral Sclerosis, Animals, Cytoplasm, Cytoplasmic Granules, Gene Expression, HeLa Cells, Humans, Mutagenesis, Insertional, Nuclear Envelope, Nucleocytoplasmic Transport Proteins, Phytic Acid, Point Mutation, Protein Aggregates, Protein Isoforms, RNA, Small Interfering
Show Abstract · Added February 15, 2016
Amyotrophic lateral sclerosis (ALS) is a lethal late onset motor neuron disease with underlying cellular defects in RNA metabolism. In prior studies, two deleterious heterozygous mutations in the gene encoding human (h)Gle1 were identified in ALS patients. hGle1 is an mRNA processing modulator that requires inositol hexakisphosphate (IP) binding for function. Interestingly, one hGLE1 mutation (c.1965-2A>C) results in a novel 88 amino acid C-terminal insertion, generating an altered protein. Like hGle1A, at steady state, the altered protein termed hGle1-IVS14-2A>C is absent from the nuclear envelope rim and localizes to the cytoplasm. hGle1A performs essential cytoplasmic functions in translation and stress granule regulation. Therefore, we speculated that the ALS disease pathology results from altered cellular pools of hGle1 and increased cytoplasmic hGle1 activity. GFP-hGle1-IVS14-2A>C localized to stress granules comparably to GFP-hGle1A, and rescued stress granule defects following siRNA-mediated hGle1 depletion. As described for hGle1A, overexpression of the hGle1-IVS14-2A>C protein also induced formation of larger SGs. Interestingly, hGle1A and the disease associated hGle1-IVS14-2A>C overexpression induced the formation of distinct cytoplasmic protein aggregates that appear similar to those found in neurodegenerative diseases. Strikingly, the ALS-linked hGle1-IVS14-2A>C protein also rescued mRNA export defects upon depletion of endogenous hGle1, acting in a potentially novel bi-functional manner. We conclude that the ALS-linked hGle1-c.1965-2A>C mutation generates a protein isoform capable of both hGle1A- and hGle1B-ascribed functions, and thereby uncoupled from normal mechanisms of hGle1 regulation.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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15 MeSH Terms
Microtubules Negatively Regulate Insulin Secretion in Pancreatic β Cells.
Zhu X, Hu R, Brissova M, Stein RW, Powers AC, Gu G, Kaverina I
(2015) Dev Cell 34: 656-68
MeSH Terms: Animals, Cells, Cultured, Cytoplasmic Granules, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Female, Glucose, Insulin, Insulin Secretion, Insulin-Secreting Cells, Mice, Microtubules, Sweetening Agents
Show Abstract · Added October 15, 2015
For glucose-stimulated insulin secretion (GSIS), insulin granules have to be localized close to the plasma membrane. The role of microtubule-dependent transport in granule positioning and GSIS has been debated. Here, we report that microtubules, counterintuitively, restrict granule availability for secretion. In β cells, microtubules originate at the Golgi and form a dense non-radial meshwork. Non-directional transport along these microtubules limits granule dwelling at the cell periphery, restricting granule availability for secretion. High glucose destabilizes microtubules, decreasing their density; such local microtubule depolymerization is necessary for GSIS, likely because granule withdrawal from the cell periphery becomes inefficient. Consistently, microtubule depolymerization by nocodazole blocks granule withdrawal, increases their concentration at exocytic sites, and dramatically enhances GSIS in vitro and in mice. Furthermore, glucose-driven MT destabilization is balanced by new microtubule formation, which likely prevents over-secretion. Importantly, microtubule density is greater in dysfunctional β cells of diabetic mice.
Copyright © 2015 Elsevier Inc. All rights reserved.
1 Communities
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13 MeSH Terms
Cytoplasmic hGle1A regulates stress granules by modulation of translation.
Aditi , Folkmann AW, Wente SR
(2015) Mol Biol Cell 26: 1476-90
MeSH Terms: Cell Line, Cytoplasmic Granules, Down-Regulation, Humans, Nucleocytoplasmic Transport Proteins, Protein Biosynthesis, Protein Isoforms, Stress, Physiological
Show Abstract · Added February 15, 2016
When eukaryotic cells respond to stress, gene expression pathways change to selectively export and translate subsets of mRNAs. Translationally repressed mRNAs accumulate in cytoplasmic foci known as stress granules (SGs). SGs are in dynamic equilibrium with the translational machinery, but mechanisms controlling this are unclear. Gle1 is required for DEAD-box protein function during mRNA export and translation. We document that human Gle1 (hGle1) is a critical regulator of translation during stress. hGle1 is recruited to SGs, and hGLE1 small interfering RNA-mediated knockdown perturbs SG assembly, resulting in increased numbers of smaller SGs. The rate of SG disassembly is also delayed. Furthermore, SG hGle1-depletion defects correlate with translation perturbations, and the hGle1 role in SGs is independent of mRNA export. Interestingly, we observe isoform-specific roles for hGle1 in which SG function requires hGle1A, whereas mRNA export requires hGle1B. We find that the SG defects in hGle1-depleted cells are rescued by puromycin or DDX3 expression. Together with recent links of hGLE1 mutations in amyotrophic lateral sclerosis patients, these results uncover a paradigm for hGle1A modulating the balance between translation and SGs during stress and disease.
© 2015 Aditi et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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8 MeSH Terms
Glycolytic enzymes localize to ribonucleoprotein granules in Drosophila germ cells, bind Tudor and protect from transposable elements.
Gao M, Thomson TC, Creed TM, Tu S, Loganathan SN, Jackson CA, McCluskey P, Lin Y, Collier SE, Weng Z, Lasko P, Ohi MD, Arkov AL
(2015) EMBO Rep 16: 379-86
MeSH Terms: Animals, Animals, Genetically Modified, Base Sequence, Cytoplasmic Granules, DNA Transposable Elements, Drosophila, Drosophila Proteins, Germ Cells, Glycolysis, Membrane Transport Proteins, MicroRNAs, Molecular Sequence Data, Ribonucleoproteins, Sequence Analysis, DNA
Show Abstract · Added January 5, 2016
Germ cells give rise to all cell lineages in the next-generation and are responsible for the continuity of life. In a variety of organisms, germ cells and stem cells contain large ribonucleoprotein granules. Although these particles were discovered more than 100 years ago, their assembly and functions are not well understood. Here we report that glycolytic enzymes are components of these granules in Drosophila germ cells and both their mRNAs and the enzymes themselves are enriched in germ cells. We show that these enzymes are specifically required for germ cell development and that they protect their genomes from transposable elements, providing the first link between metabolism and transposon silencing. We further demonstrate that in the granules, glycolytic enzymes associate with the evolutionarily conserved Tudor protein. Our biochemical and single-particle EM structural analyses of purified Tudor show a flexible molecule and suggest a mechanism for the recruitment of glycolytic enzymes to the granules. Our data indicate that germ cells, similarly to stem cells and tumor cells, might prefer to produce energy through the glycolytic pathway, thus linking a particular metabolism to pluripotency.
© 2015 The Authors.
1 Communities
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14 MeSH Terms
The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules.
Yasuda K, Zhang H, Loiselle D, Haystead T, Macara IG, Mili S
(2013) J Cell Biol 203: 737-46
MeSH Terms: Adenomatous Polyposis Coli Protein, Animals, Cytoplasmic Granules, Mice, NIH 3T3 Cells, Protein Biosynthesis, RNA, Messenger, RNA-Binding Protein FUS, Ribonucleoproteins
Show Abstract · Added March 20, 2014
RNA localization pathways direct numerous mRNAs to distinct subcellular regions and affect many physiological processes. In one such pathway the tumor-suppressor protein adenomatous polyposis coli (APC) targets RNAs to cell protrusions, forming APC-containing ribonucleoprotein complexes (APC-RNPs). Here, we show that APC-RNPs associate with the RNA-binding protein Fus/TLS (fused in sarcoma/translocated in liposarcoma). Fus is not required for APC-RNP localization but is required for efficient translation of associated transcripts. Labeling of newly synthesized proteins revealed that Fus promotes translation preferentially within protrusions. Mutations in Fus cause amyotrophic lateral sclerosis (ALS) and the mutant protein forms inclusions that appear to correspond to stress granules. We show that overexpression or mutation of Fus results in formation of granules, which preferentially recruit APC-RNPs. Remarkably, these granules are not translationally silent. Instead, APC-RNP transcripts are translated within cytoplasmic Fus granules. These results unexpectedly show that translation can occur within stress-like granules. Importantly, they identify a new local function for cytoplasmic Fus with implications for ALS pathology.
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9 MeSH Terms
Paneth cell ablation in the presence of Klebsiella pneumoniae induces necrotizing enterocolitis (NEC)-like injury in the small intestine of immature mice.
Zhang C, Sherman MP, Prince LS, Bader D, Weitkamp JH, Slaughter JC, McElroy SJ
(2012) Dis Model Mech 5: 522-32
MeSH Terms: Aging, Animals, Cell Differentiation, Cytoplasmic Granules, Disease Models, Animal, Dithizone, Enteral Nutrition, Enterocolitis, Necrotizing, Humans, Infant, Newborn, Inflammation, Intestine, Small, Klebsiella pneumoniae, Mice, Paneth Cells, Zinc
Show Abstract · Added February 27, 2014
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. During NEC pathogenesis, bacteria are able to penetrate innate immune defenses and invade the intestinal epithelial layer, causing subsequent inflammation and tissue necrosis. Normally, Paneth cells appear in the intestinal crypts during the first trimester of human pregnancy. Paneth cells constitute a major component of the innate immune system by producing multiple antimicrobial peptides and proinflammatory mediators. To better understand the possible role of Paneth cell disruption in NEC, we quantified the number of Paneth cells present in infants with NEC and found that they were significantly decreased compared with age-matched controls. We were able to model this loss in the intestine of postnatal day (P)14-P16 (immature) mice by treating them with the zinc chelator dithizone. Intestines from dithizone-treated animals retained approximately half the number of Paneth cells compared with controls. Furthermore, by combining dithizone treatment with exposure to Klebsiella pneumoniae, we were able to induce intestinal injury and inflammatory induction that resembles human NEC. Additionally, this novel Paneth cell ablation model produces NEC-like pathology that is consistent with other currently used animal models, but this technique is simpler to use, can be used in older animals that have been dam fed, and represents a novel line of investigation to study NEC pathogenesis and treatment.
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16 MeSH Terms
Mutations in the RNA granule component TDRD7 cause cataract and glaucoma.
Lachke SA, Alkuraya FS, Kneeland SC, Ohn T, Aboukhalil A, Howell GR, Saadi I, Cavallesco R, Yue Y, Tsai AC, Nair KS, Cosma MI, Smith RS, Hodges E, Alfadhli SM, Al-Hajeri A, Shamseldin HE, Behbehani A, Hannon GJ, Bulyk ML, Drack AV, Anderson PJ, John SW, Maas RL
(2011) Science 331: 1571-6
MeSH Terms: Animals, Cataract, Cell Line, Chick Embryo, Crystallins, Cytoplasmic Granules, Embryonic Development, Female, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Glaucoma, Humans, Hypospadias, Lens, Crystalline, Male, Mice, Mutation, Organogenesis, Protein Biosynthesis, RNA, Messenger, RNA-Binding Proteins, Ribonucleoproteins, Spermatogenesis
Show Abstract · Added February 15, 2016
The precise transcriptional regulation of gene expression is essential for vertebrate development, but the role of posttranscriptional regulatory mechanisms is less clear. Cytoplasmic RNA granules (RGs) function in the posttranscriptional control of gene expression, but the extent of RG involvement in organogenesis is unknown. We describe two human cases of pediatric cataract with loss-of-function mutations in TDRD7 and demonstrate that Tdrd7 nullizygosity in mouse causes cataracts, as well as glaucoma and an arrest in spermatogenesis. TDRD7 is a Tudor domain RNA binding protein that is expressed in lens fiber cells in distinct TDRD7-RGs that interact with STAU1-ribonucleoproteins (RNPs). TDRD7 coimmunoprecipitates with specific lens messenger RNAs (mRNAs) and is required for the posttranscriptional control of mRNAs that are critical to normal lens development and to RG function. These findings demonstrate a role for RGs in vertebrate organogenesis.
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23 MeSH Terms
Activation of protein kinase R is required for induction of stress granules by respiratory syncytial virus but dispensable for viral replication.
Lindquist ME, Mainou BA, Dermody TS, Crowe JE
(2011) Virology 413: 103-10
MeSH Terms: Cell Line, Cytoplasmic Granules, Enzyme Activation, Humans, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, Virus Replication, eIF-2 Kinase
Show Abstract · Added December 10, 2013
We performed experiments to determine the effect of PKR activation on respiratory syncytial virus (RSV) replication. We first determined that RSV infection activates PKR which induces the phosphorylation of eIF2α, resulting in the formation of host stress granules. We used RNA interference to decrease endogenous PKR levels. RSV replication was not altered in cells deficient for PKR expression. However, RSV-mediated stress granule formation was significantly reduced in PKR-knockdown cells. As an alternative method to block PKR activation, we used treatment with the kinase inhibitor 2-aminopurine (2-AP). We observed that 2-AP treatment significantly reduced viral replication. We also treated PKR-knockdown cells with 2-AP and inoculated with RSV. Under these conditions, 2-AP treatment diminished viral replication in the absence of PKR expression. These results suggest that PKR activation has a minimal effect on RSV replication and that the antiviral effect of 2-AP during RSV infection likely occurs via a PKR-independent mechanism.
Copyright © 2011 Elsevier Inc. All rights reserved.
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2 Members
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8 MeSH Terms
Respiratory syncytial virus induces host RNA stress granules to facilitate viral replication.
Lindquist ME, Lifland AW, Utley TJ, Santangelo PJ, Crowe JE
(2010) J Virol 84: 12274-84
MeSH Terms: Antigens, Surface, Blotting, Western, Carrier Proteins, Cell Line, Cytoplasmic Granules, DNA Helicases, ELAV Proteins, ELAV-Like Protein 1, Epithelial Cells, Humans, Poly-ADP-Ribose Binding Proteins, RNA Helicases, RNA Interference, RNA Recognition Motif Proteins, RNA, Messenger, RNA-Binding Proteins, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, Reverse Transcriptase Polymerase Chain Reaction, Stress, Physiological, Virus Replication
Show Abstract · Added August 6, 2012
Mammalian cell cytoplasmic RNA stress granules are induced during various conditions of stress and are strongly associated with regulation of host mRNA translation. Several viruses induce stress granules during the course of infection, but the exact function of these structures during virus replication is not well understood. In this study, we showed that respiratory syncytial virus (RSV) induced host stress granules in epithelial cells during the course of infection. We also showed that stress granules are distinct from cytoplasmic viral inclusion bodies and that the RNA binding protein HuR, normally found in stress granules, also localized to viral inclusion bodies during infection. Interestingly, we demonstrated that infected cells containing stress granules also contained more RSV protein than infected cells that did not form inclusion bodies. To address the role of stress granule formation in RSV infection, we generated a stable epithelial cell line with reduced expression of the Ras-GAP SH3 domain-binding protein (G3BP) that displayed an inhibited stress granule response. Surprisingly, RSV replication was impaired in these cells compared to its replication in cells with intact G3BP expression. In contrast, knockdown of HuR by RNA interference did not affect stress granule formation or RSV replication. Finally, using RNA probes specific for RSV genomic RNA, we found that viral RNA predominantly localized to viral inclusion bodies but a small percentage also interacted with stress granules during infection. These results suggest that RSV induces a host stress granule response and preferentially replicates in host cells that have committed to a stress response.
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21 MeSH Terms