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Müller glial microRNAs are required for the maintenance of glial homeostasis and retinal architecture.
Wohl SG, Jorstad NL, Levine EM, Reh TA
(2017) Nat Commun 8: 1603
MeSH Terms: 3T3 Cells, Animals, Cell Movement, Cells, Cultured, DEAD-box RNA Helicases, Ependymoglial Cells, Gene Expression Profiling, Homeostasis, Mice, Mice, Knockout, Mice, Transgenic, MicroRNAs, Microscopy, Confocal, Neuroglia, Retina, Ribonuclease III
Show Abstract · Added February 14, 2018
To better understand the roles of microRNAs in glial function, we used a conditional deletion of Dicer1 (Dicer-CKO) in retinal Müller glia (MG). Dicer1 deletion from the MG leads to an abnormal migration of the cells as early as 1 month after the deletion. By 6 months after Dicer1 deletion, the MG form large aggregations and severely disrupt normal retinal architecture and function. The most highly upregulated gene in the Dicer-CKO MG is the proteoglycan Brevican (Bcan) and overexpression of Bcan results in similar aggregations of the MG in wild-type retina. One potential microRNA that regulates Bcan is miR-9, and overexpression of miR-9 can partly rescue the effects of Dicer1 deletion on the MG phenotype. We also find that MG from retinitis pigmentosa patients display an increase in Brevican immunoreactivity at sites of MG aggregation, linking the retinal remodeling that occurs in chronic disease with microRNAs.
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16 MeSH Terms
Iron Toxicity in the Retina Requires Alu RNA and the NLRP3 Inflammasome.
Gelfand BD, Wright CB, Kim Y, Yasuma T, Yasuma R, Li S, Fowler BJ, Bastos-Carvalho A, Kerur N, Uittenbogaard A, Han YS, Lou D, Kleinman ME, McDonald WH, Núñez G, Georgel P, Dunaief JL, Ambati J
(2015) Cell Rep 11: 1686-93
MeSH Terms: Alu Elements, Animals, Carrier Proteins, Caspase 1, DEAD-box RNA Helicases, Inflammasomes, Iron, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, RNA-Binding Proteins, Retinal Pigment Epithelium, Ribonuclease III
Show Abstract · Added January 26, 2016
Excess iron induces tissue damage and is implicated in age-related macular degeneration (AMD). Iron toxicity is widely attributed to hydroxyl radical formation through Fenton's reaction. We report that excess iron, but not other Fenton catalytic metals, induces activation of the NLRP3 inflammasome, a pathway also implicated in AMD. Additionally, iron-induced degeneration of the retinal pigmented epithelium (RPE) is suppressed in mice lacking inflammasome components caspase-1/11 or Nlrp3 or by inhibition of caspase-1. Iron overload increases abundance of RNAs transcribed from short interspersed nuclear elements (SINEs): Alu RNAs and the rodent equivalent B1 and B2 RNAs, which are inflammasome agonists. Targeting Alu or B2 RNA prevents iron-induced inflammasome activation and RPE degeneration. Iron-induced SINE RNA accumulation is due to suppression of DICER1 via sequestration of the co-factor poly(C)-binding protein 2 (PCBP2). These findings reveal an unexpected mechanism of iron toxicity, with implications for AMD and neurodegenerative diseases associated with excess iron.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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13 MeSH Terms
Gonadotrope-specific deletion of Dicer results in severely suppressed gonadotropins and fertility defects.
Wang H, Graham I, Hastings R, Gunewardena S, Brinkmeier ML, Conn PM, Camper SA, Kumar TR
(2015) J Biol Chem 290: 2699-714
MeSH Terms: Animals, DEAD-box RNA Helicases, Female, Fertility, Gonadotrophs, Gonadotropins, Male, Mice, Mice, Knockout, MicroRNAs, Rats, Real-Time Polymerase Chain Reaction, Ribonuclease III
Show Abstract · Added February 19, 2015
Pituitary gonadotropins follicle-stimulating hormone and luteinizing hormone are heterodimeric glycoproteins expressed in gonadotropes. They act on gonads and promote their development and functions including steroidogenesis and gametogenesis. Although transcriptional regulation of gonadotropin subunits has been well studied, the post-transcriptional regulation of gonadotropin subunits is not well understood. To test if microRNAs regulate the hormone-specific gonadotropin β subunits in vivo, we deleted Dicer in gonadotropes by a Cre-lox genetic approach. We found that many of the DICER-dependent microRNAs, predicted in silico to bind gonadotropin β subunit mRNAs, were suppressed in purified gonadotropes of mutant mice. Loss of DICER-dependent microRNAs in gonadotropes resulted in profound suppression of gonadotropin-β subunit proteins and, consequently, the heterodimeric hormone secretion. In addition to suppression of basal levels, interestingly, the post-gonadectomy-induced rise in pituitary gonadotropin synthesis and secretion were both abolished in mutants, indicating a defective gonadal negative feedback control. Furthermore, mutants lacking Dicer in gonadotropes displayed severely reduced fertility and were rescued with exogenous hormones confirming that the fertility defects were secondary to suppressed gonadotropins. Our studies reveal that DICER-dependent microRNAs are essential for gonadotropin homeostasis and fertility in mice. Our studies also implicate microRNAs in gonadal feedback control of gonadotropin synthesis and secretion. Thus, DICER-dependent microRNAs confer a new layer of transcriptional and post-transcriptional regulation in gonadotropes to orchestrate the hypothalamus-pituitary-gonadal axis physiology.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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13 MeSH Terms
microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells.
Marcais A, Blevins R, Graumann J, Feytout A, Dharmalingam G, Carroll T, Amado IF, Bruno L, Lee K, Walzer T, Mann M, Freitas AA, Boothby M, Fisher AG, Merkenschlager M
(2014) J Exp Med 211: 2281-95
MeSH Terms: Animals, Base Sequence, Binding Sites, CD4-Positive T-Lymphocytes, Clonal Anergy, Gene Expression Regulation, Humans, Interleukin-2, Lymphocyte Activation, Mice, Mice, Transgenic, MicroRNAs, Phosphorylation, Proto-Oncogene Proteins c-akt, Receptors, Antigen, T-Cell, Ribonuclease III, Signal Transduction, TOR Serine-Threonine Kinases
Show Abstract · Added February 15, 2016
T cell receptor (TCR) signals can elicit full activation with acquisition of effector functions or a state of anergy. Here, we ask whether microRNAs affect the interpretation of TCR signaling. We find that Dicer-deficient CD4 T cells fail to correctly discriminate between activating and anergy-inducing stimuli and produce IL-2 in the absence of co-stimulation. Excess IL-2 production by Dicer-deficient CD4 T cells was sufficient to override anergy induction in WT T cells and to restore inducible Foxp3 expression in Il2-deficient CD4 T cells. Phosphorylation of Akt on S473 and of S6 ribosomal protein was increased and sustained in Dicer-deficient CD4 T cells, indicating elevated mTOR activity. The mTOR components Mtor and Rictor were posttranscriptionally deregulated, and the microRNAs Let-7 and miR-16 targeted the Mtor and Rictor mRNAs. Remarkably, returning Mtor and Rictor to normal levels by deleting one allele of Mtor and one allele of Rictor was sufficient to reduce Akt S473 phosphorylation and to reduce co-stimulation-independent IL-2 production in Dicer-deficient CD4 T cells. These results show that microRNAs regulate the expression of mTOR components in T cells, and that this regulation is critical for the modulation of mTOR activity. Hence, microRNAs contribute to the discrimination between T cell activation and anergy.
© 2014 Marcais et al.
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18 MeSH Terms
Dynamic miRNA expression patterns during retinal regeneration in zebrafish: reduced dicer or miRNA expression suppresses proliferation of Müller glia-derived neuronal progenitor cells.
Rajaram K, Harding RL, Bailey T, Patton JG, Hyde DR
(2014) Dev Dyn 243: 1591-605
MeSH Terms: Animals, Cell Proliferation, Gene Expression Regulation, Gene Knockdown Techniques, MicroRNAs, Neural Stem Cells, Neuroglia, Regeneration, Retina, Ribonuclease III, Zebrafish, Zebrafish Proteins
Show Abstract · Added January 20, 2015
BACKGROUND - Adult zebrafish spontaneously regenerate their retinas after damage. Although a number of genes and signaling pathways involved in regeneration have been identified, the exact mechanisms regulating various aspects of regeneration are unclear. microRNAs (miRNAs) were examined for their potential roles in regulating zebrafish retinal regeneration.
RESULTS - To investigate the requirement of miRNAs during zebrafish retinal regeneration, we knocked down the expression of Dicer in retinas prior to light-induced damage. Reduced Dicer expression significantly decreased the number of proliferating Müller glia-derived neuronal progenitor cells during regeneration. To identify individual miRNAs with roles in neuronal progenitor cell proliferation, we collected retinas at different stages of light damage and performed small RNA high-throughput sequencing. We identified subsets of miRNAs that were differentially expressed during active regeneration but returned to basal levels once regeneration was completed. We then knocked down five different miRNAs that increased in expression and assessed the effects on retinal regeneration. Reduction of miR-142b and miR-146a expression significantly reduced INL proliferation at 51 h of light treatment, while knockdown of miR-7a, miR-27c, and miR-31 expression significantly reduced INL proliferation at 72 h of constant light.
CONCLUSIONS - miRNAs exhibit dynamic expression profiles during retinal regeneration and are necessary for neuronal progenitor cell proliferation.
© 2014 The Authors. Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
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Inactivation of p53 is insufficient to allow B cells and B-cell lymphomas to survive without Dicer.
Adams CM, Eischen CM
(2014) Cancer Res 74: 3923-34
MeSH Terms: Animals, Antigens, CD19, B-Lymphocytes, Cell Survival, Cell Transformation, Neoplastic, Female, Gene Deletion, Gene Expression, Gene Silencing, Genes, myc, Lymphoma, B-Cell, Mice, Mice, Knockout, Phenotype, Ribonuclease III, Tumor Suppressor Protein p53
Show Abstract · Added May 27, 2014
Inactivation of p53, the master regulator of cellular stress and damage signals, often allows cells that should die or senesce to live. Loss of Dicer, an RNase III-like enzyme critical in microRNA biogenesis, causes embryonic lethality and activation of the p53 pathway. Several nonhematopoietic cell types that contain inactivated p53 have been shown to survive Dicer deletion, suggesting that p53 loss may protect cells from the negative consequences of Dicer deletion. However, here, we report that loss of p53 did not provide a survival advantage to B cells, as they underwent rapid apoptosis upon Dicer deletion. Moreover, a deficiency in p53 neither rescued the Dicer deletion-induced delay in Myc-driven B-cell lymphomagenesis, nor allowed a single B-cell lymphoma to develop with biallelic deletion of Dicer. A p53 deficiency did, however, restore the pre-B/B-cell phenotype and CD19 surface expression of the lymphomas that emerged in conditional Dicer knockout Eμ-myc transgenic mice. Moreover, p53 loss in transformed B cells did not confer protection from apoptosis, as Dicer deletion in established p53-null B-cell lymphomas induced apoptosis, and all of the 1,260 B-cell lymphoma clones analyzed that survived Cre-mediated Dicer deletion retained at least one allele of Dicer. Moreover, Dicer deletion in lymphomas in vivo reduced tumor burden and prolonged survival. Therefore, inactivation of p53 is insufficient to allow untransformed B cells and B-cell lymphomas to survive without Dicer, presenting a potential therapeutic opportunity for the treatment of B-cell lymphomas.
©2014 American Association for Cancer Research.
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16 MeSH Terms
The regulatory effect of miRNAs is a heritable genetic trait in humans.
Geeleher P, Huang SR, Gamazon ER, Golden A, Seoighe C
(2012) BMC Genomics 13: 383
MeSH Terms: Algorithms, Gene Expression Profiling, Gene Expression Regulation, Genome, Human, Genome-Wide Association Study, HapMap Project, Humans, Inheritance Patterns, MicroRNAs, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Ribonuclease III
Show Abstract · Added April 13, 2017
BACKGROUND - microRNAs (miRNAs) have been shown to regulate the expression of a large number of genes and play key roles in many biological processes. Several previous studies have quantified the inhibitory effect of a miRNA indirectly by considering the expression levels of genes that are predicted to be targeted by the miRNA and this approach has been shown to be robust to the choice of prediction algorithm. Given a gene expression dataset, Cheng et al. defined the regulatory effect score (RE-score) of a miRNA as the difference in the gene expression rank of targets of the miRNA compared to non-targeted genes.
RESULTS - Using microarray data from parent-offspring trios from the International HapMap project, we show that the RE-score of most miRNAs is correlated between parents and offspring and, thus, inter-individual variation in RE-score has a genetic component in humans. Indeed, the mean RE-score across miRNAs is correlated between parents and offspring, suggesting genetic differences in the overall efficiency of the miRNA biogenesis pathway between individuals. To explore the genetics of this quantitative trait further, we carried out a genome-wide association study of the mean RE-score separately in two HapMap populations (CEU and YRI). No genome-wide significant associations were discovered; however, a SNP rs17409624, in an intron of DROSHA, was significantly associated with mean RE-score in the CEU population following permutation-based control for multiple testing based on all SNPs mapped to the canonical miRNA biogenesis pathway; of 244 individual miRNA RE-scores assessed in the CEU, 214 were associated (p < 0.05) with rs17409624. The SNP was also nominally significantly associated (p = 0.04) with mean RE-score in the YRI population. Interestingly, the same SNP was associated with 17 (8.5% of all expressed) miRNA expression levels in the CEU. We also show here that the expression of the targets of most miRNAs is more highly correlated with global changes in miRNA regulatory effect than with the expression of the miRNA itself.
CONCLUSIONS - We present evidence that miRNA regulatory effect is a heritable trait in humans and that a polymorphism of the DROSHA gene contributes to the observed inter-individual differences.
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Inducible deletion of epidermal Dicer and Drosha reveals multiple functions for miRNAs in postnatal skin.
Teta M, Choi YS, Okegbe T, Wong G, Tam OH, Chong MM, Seykora JT, Nagy A, Littman DR, Andl T, Millar SE
(2012) Development 139: 1405-16
MeSH Terms: Animals, Crosses, Genetic, DEAD-box RNA Helicases, Epidermal Cells, Gene Deletion, Hair Follicle, Mice, MicroRNAs, Microscopy, Fluorescence, Phenotype, Ribonuclease III, Signal Transduction, Skin, Stem Cells, Wound Healing
Show Abstract · Added January 30, 2013
MicroRNAs (miRNAs) regulate the expression of many mammalian genes and play key roles in embryonic hair follicle development; however, little is known of their functions in postnatal hair growth. We compared the effects of deleting the essential miRNA biogenesis enzymes Drosha and Dicer in mouse skin epithelial cells at successive postnatal time points. Deletion of either Drosha or Dicer during an established growth phase (anagen) caused failure of hair follicles to enter a normal catagen regression phase, eventual follicular degradation and stem cell loss. Deletion of Drosha or Dicer in resting phase follicles did not affect follicular structure or epithelial stem cell maintenance, and stimulation of anagen by hair plucking caused follicular proliferation and formation of a primitive transient amplifying matrix population. However, mutant matrix cells exhibited apoptosis and DNA damage and hair follicles rapidly degraded. Hair follicle defects at early time points post-deletion occurred in the absence of inflammation, but a dermal inflammatory response and hyperproliferation of interfollicular epidermis accompanied subsequent hair follicle degradation. These data reveal multiple functions for Drosha and Dicer in suppressing DNA damage in rapidly proliferating follicular matrix cells, facilitating catagen and maintaining follicular structures and their associated stem cells. Although Drosha and Dicer each possess independent non-miRNA-related functions, the similarity in phenotypes of the inducible epidermal Drosha and Dicer mutants indicates that these defects result primarily from failure of miRNA processing. Consistent with this, Dicer deletion resulted in the upregulation of multiple direct targets of the highly expressed epithelial miRNA miR-205.
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15 MeSH Terms
MicroRNA biogenesis is required for Myc-induced B-cell lymphoma development and survival.
Arrate MP, Vincent T, Odvody J, Kar R, Jones SN, Eischen CM
(2010) Cancer Res 70: 6083-92
MeSH Terms: Alleles, Animals, Cell Transformation, Neoplastic, DEAD-box RNA Helicases, Endoribonucleases, Gene Deletion, Genes, myc, Genes, p53, Lymphoma, B-Cell, Mice, Mice, Knockout, MicroRNAs, Ribonuclease III
Show Abstract · Added March 5, 2014
Many tumor cells express globally reduced levels of microRNAs (miRNA), suggesting that decreased miRNA expression in premalignant cells contributes to their tumorigenic phenotype. In support of this, Dicer, an RNase III-like enzyme that controls the maturation of miRNA, was recently shown to function as a haploinsufficient tumor suppressor in nonhematopoietic cells. Because the Myc oncoprotein, a critical inducer of B-cell lymphomas, was reported to suppress the expression of multiple miRNAs in lymphoma cells, it was presumed that a deficiency of Dicer and subsequent loss of miRNA maturation would accelerate Myc-induced lymphoma development. We report here that, surprisingly, a haploinsufficiency of Dicer in B cells failed to promote B-cell malignancy or accelerate Myc-induced B-cell lymphomagenesis in mice. Moreover, deletion of Dicer in B cells of CD19-cre(+)/Emicro-myc mice significantly inhibited lymphomagenesis, and all lymphomas that did arise in these mice lacked functional Cre expression and retained at least one functional Dicer allele. Uncharacteristically, the lymphomas that frequently developed in the CD19-cre(+)/Dicer(fl/fl)/Emicro-myc mice were of very early precursor B-cell origin, a stage of B-cell development prior to Cre expression. Therefore, loss of Dicer function was not advantageous for lymphomagenesis, but rather, Dicer ablation was strongly selected against during Myc-induced B-cell lymphoma development. Moreover, deletion of Dicer in established B-cell lymphomas resulted in apoptosis, revealing that Dicer is required for B-cell lymphoma survival. Thus, Dicer does not function as a haploinsufficient tumor suppressor in B cells and is required for B-cell lymphoma development and survival.
(c)2010 AACR.
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Targeted deletion of Dicer from proximal tubules protects against renal ischemia-reperfusion injury.
Wei Q, Bhatt K, He HZ, Mi QS, Haase VH, Dong Z
(2010) J Am Soc Nephrol 21: 756-61
MeSH Terms: Acute Kidney Injury, Animals, DEAD-box RNA Helicases, Endoribonucleases, Gene Knockout Techniques, Kidney Tubules, Proximal, Male, Mice, Mice, Knockout, MicroRNAs, Oligonucleotide Array Sequence Analysis, Reperfusion Injury, Ribonuclease III
Show Abstract · Added August 19, 2013
MicroRNAs are endogenous, noncoding, small RNAs that regulate expression and function of genes, but little is known about regulation of microRNA in the kidneys under normal or pathologic states. Here, we generated a mouse model in which the proximal tubular cells lack Dicer, a key enzyme for microRNA production. These mice had normal renal function and histology under control conditions despite a global downregulation of microRNAs in the renal cortex; however, these animals were remarkably resistant to renal ischemia-reperfusion injury (IRI), showing significantly better renal function, less tissue damage, lower tubular apoptosis, and improved survival compared with their wild-type littermates. Microarray analysis showed altered expression of specific microRNAs during renal IRI. Taken together, these results demonstrate evidence for a pathogenic role of Dicer and associated microRNAs in renal IRI.
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13 MeSH Terms