{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T22:15:17Z","timestamp":1780524917138,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.pntd.0009425","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000}}],"reference-count":98,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["HBF-143163"],"award-info":[{"award-number":["HBF-143163"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-148704"],"award-info":[{"award-number":["PJT-148704"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP-56974"],"award-info":[{"award-number":["MOP-56974"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"crossref","award":["Doctoral fellowship"],"award-info":[{"award-number":["Doctoral fellowship"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Brazilian National Science Council (CNPq","award":["465425\/2014-3; 439976\/2016-2; 440423\/2016-3; 25036"],"award-info":[{"award-number":["465425\/2014-3; 439976\/2016-2; 440423\/2016-3; 25036"]}]},{"name":"Brazilian National Science Council (CNPq)","award":["425359\/2018-2"],"award-info":[{"award-number":["425359\/2018-2"]}]},{"name":"Minas Gerais Foundation for Science (FAPEMIG)","award":["23888"],"award-info":[{"award-number":["23888"]}]},{"name":"Comissao de Apoio a Pessoal de Ensino Superior (CAPES)","award":["88881.130741\/2016-01; 88887.136428\/2017-00; 88887.130735\/2016-00"],"award-info":[{"award-number":["88881.130741\/2016-01; 88887.136428\/2017-00; 88887.130735\/2016-00"]}]},{"DOI":"10.13039\/100010686","name":"H2020 European Institute of Innovation and Technology","doi-asserted-by":"publisher","award":["ZIKAlliance 734548"],"award-info":[{"award-number":["ZIKAlliance 734548"]}],"id":[{"id":"10.13039\/100010686","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jewish General Hospital Foundation","award":["Equipment"],"award-info":[{"award-number":["Equipment"]}]},{"name":"Soci\u00e9t\u00e9 d'Entreprise et de Gestion","award":["Doctoral fellowship"],"award-info":[{"award-number":["Doctoral fellowship"]}]},{"name":"McGill Integrated Cancer Research Training Program","award":["Doctoral fellowship"],"award-info":[{"award-number":["Doctoral fellowship"]}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>Zika virus (ZIKV) infection of neurons leads to neurological complications and congenital malformations of the brain of neonates. To date, ZIKV mechanism of infection and pathogenesis is not entirely understood and different studies on gene regulation of ZIKV-infected cells have identified a dysregulation of inflammatory and stem cell maintenance pathways. MicroRNAs (miRNAs) are post-transcriptional regulators of cellular genes and they contribute to cell development in normal function and disease. Previous reports with integrative analyses of messenger RNAs (mRNAs) and miRNAs during ZIKV infection have not identified neurological pathway defects. We hypothesized that dysregulation of pathways involved in neurological functions will be identified by RNA profiling of ZIKV-infected fetal neurons. We therefore used microarrays to analyze gene expression levels following ZIKV infection of fetal murine neurons. We observed that the expression levels of transcription factors such as neural PAS domain protein 4 (Npas4) and of three members of the orphan nuclear receptor 4 (Nr4a) were severely decreased after viral infection. We confirmed that their downregulation was at both the mRNA level and at the protein level. The dysregulation of these transcription factors has been previously linked to aberrant neural functions and development. We next examined the miRNA expression profile in infected primary murine neurons by microarray and found that various miRNAs were dysregulated upon ZIKV infection. An integrative analysis of the differentially expressed miRNAs and mRNAs indicated that miR-7013-5p targets Nr4a3 gene. Using miRmimics, we corroborated that miR-7013-5p downregulates Nr4a3 mRNA and protein levels. Our data identify a profound dysregulation of neural transcription factors with an overexpression of miR-7013-5p that results in decreased Nr4a3 expression, likely a main contributor to ZIKV-induced neuronal dysfunction.<\/jats:p>","DOI":"10.1371\/journal.pntd.0009425","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T19:55:09Z","timestamp":1622231709000},"page":"e0009425","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Profound downregulation of neural transcription factor Npas4 and Nr4a family in fetal mice neurons infected with Zika virus"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5958-2880","authenticated-orcid":true,"given":"Sergio P.","family":"Alpuche-Lazcano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0450-9616","authenticated-orcid":true,"given":"James","family":"Saliba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0175-642X","authenticated-orcid":true,"given":"Vivian V.","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4473-3340","authenticated-orcid":true,"given":"Gabriel H.","family":"Campolina-Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9778-554X","authenticated-orcid":true,"given":"Fernanda M.","family":"Marim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8876-3827","authenticated-orcid":true,"given":"Lucas S.","family":"Ribeiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7029-2462","authenticated-orcid":true,"given":"Volker","family":"Blank","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1828-0296","authenticated-orcid":true,"given":"Andrew J.","family":"Mouland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6944-3008","authenticated-orcid":true,"given":"Mauro M.","family":"Teixeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4553-0836","authenticated-orcid":true,"given":"Anne","family":"Gatignol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"key":"pntd.0009425.ref001","doi-asserted-by":"crossref","first-page":"e69","DOI":"10.1038\/emi.2017.59","article-title":"Zika virus replication in the mosquito Culex quinquefasciatus in Brazil.","volume":"6","author":"DR Guedes","year":"2017","journal-title":"Emerg Microbes Infect"},{"key":"pntd.0009425.ref002","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/0035-9203(52)90042-4","article-title":"Zika virus. I. Isolations and serological specificity","volume":"46","author":"GW Dick","year":"1952","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"pntd.0009425.ref003","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.3201\/eid2011.141253","article-title":"Zika virus, French Polynesia, South Pacific, 2013","volume":"20","author":"WT Hancock","year":"2014","journal-title":"Emerg Infect Dis"},{"key":"pntd.0009425.ref004","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41579-018-0134-9","article-title":"The evolution of Zika virus from Asia to the Americas","volume":"17","author":"ZY Liu","year":"2019","journal-title":"Nat Rev Microbiol"},{"key":"pntd.0009425.ref005","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1017\/S0950268817001200","article-title":"On the origin and timing of Zika virus introduction in Brazil","volume":"145","author":"E Massad","year":"2017","journal-title":"Epidemiol Infect"},{"key":"pntd.0009425.ref006","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1590\/0074-02760150192","article-title":"First report of autochthonous transmission of Zika virus in Brazil","volume":"110","author":"C Zanluca","year":"2015","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"pntd.0009425.ref007","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.cll.2017.01.002","article-title":"Zika Virus.","volume":"37","author":"RF Relich","year":"2017","journal-title":"Clin Lab Med"},{"key":"pntd.0009425.ref008","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1159\/000452950","article-title":"Zika Virus-Induced Microcephaly and Its Possible Molecular Mechanism","volume":"59","author":"MI Faizan","year":"2016","journal-title":"Intervirology"},{"key":"pntd.0009425.ref009","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1056\/NEJMoa1602412","article-title":"Zika Virus Infection in Pregnant Women in Rio de Janeiro","volume":"375","author":"P Brasil","year":"2016","journal-title":"N Engl J Med"},{"key":"pntd.0009425.ref010","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.15585\/mmwr.mm6641a1","article-title":"Update: Interim Guidance for the Diagnosis, Evaluation, and Management of Infants with Possible Congenital Zika Virus Infection\u2014United States, October 2017.","volume":"66","author":"T Adebanjo","year":"2017","journal-title":"MMWR Morb Mortal Wkly Rep."},{"key":"pntd.0009425.ref011","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1056\/NEJMc1609015","article-title":"Zika Virus and the Guillain-Barre Syndrome\u2014Case Series from Seven Countries","volume":"375","author":"T Dos Santos","year":"2016","journal-title":"N Engl J Med"},{"key":"pntd.0009425.ref012","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s12974-017-0824-7","article-title":"Zika virus infection of cellular components of the blood-retinal barriers: implications for viral associated congenital ocular disease.","volume":"14","author":"T Roach","year":"2017","journal-title":"J Neuroinflammation"},{"key":"pntd.0009425.ref013","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.chom.2016.03.008","article-title":"Type III Interferons Produced by Human Placental Trophoblasts Confer Protection against Zika Virus Infection","volume":"19","author":"A Bayer","year":"2016","journal-title":"Cell Host Microbe"},{"key":"pntd.0009425.ref014","doi-asserted-by":"crossref","first-page":"e02019","DOI":"10.1128\/JVI.02019-17","article-title":"Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14\u201322","volume":"92","author":"F Cheng","year":"2018","journal-title":"J Virol"},{"key":"pntd.0009425.ref015","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.coviro.2019.01.005","article-title":"Strategies for Zika drug discovery.","volume":"35","author":"J Zou","year":"2019","journal-title":"Curr Opin Virol."},{"key":"pntd.0009425.ref016","doi-asserted-by":"crossref","first-page":"4448","DOI":"10.1021\/acs.chemrev.7b00719","article-title":"Biochemistry and Molecular Biology of Flaviviruses","volume":"118","author":"NJ Barrows","year":"2018","journal-title":"Chem Rev"},{"key":"pntd.0009425.ref017","doi-asserted-by":"crossref","first-page":"13410","DOI":"10.1038\/ncomms13410","article-title":"Structure of the NS2B-NS3 protease from Zika virus after self-cleavage.","volume":"7","author":"WW Phoo","year":"2016","journal-title":"Nat Commun."},{"key":"pntd.0009425.ref018","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.coviro.2012.02.011","article-title":"Degrees of maturity: the complex structure and biology of flaviviruses","volume":"2","author":"TC Pierson","year":"2012","journal-title":"Curr Opin Virol"},{"key":"pntd.0009425.ref019","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.tibs.2017.02.009","article-title":"Structural Biology of the Zika Virus","volume":"42","author":"Y Shi","year":"2017","journal-title":"Trends Biochem Sci"},{"key":"pntd.0009425.ref020","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.meegid.2016.05.004","article-title":"Genomic characterization and phylogenetic analysis of Zika virus circulating in the Americas","volume":"43","author":"Q Ye","year":"2016","journal-title":"Infect Genet Evol"},{"key":"pntd.0009425.ref021","doi-asserted-by":"crossref","first-page":"e0005775","DOI":"10.1371\/journal.pntd.0005775","article-title":"Zika virus inhibits eIF2alpha-dependent stress granule assembly.","volume":"11","author":"R Amorim","year":"2017","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0009425.ref022","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1016\/j.celrep.2017.02.014","article-title":"Ultrastructural Characterization of Zika Virus Replication Factories","volume":"18","author":"M Cortese","year":"2017","journal-title":"Cell Rep"},{"key":"pntd.0009425.ref023","doi-asserted-by":"crossref","first-page":"e00055","DOI":"10.1128\/MMBR.00055-16","article-title":"The Antigenic Structure of Zika Virus and Its Relation to Other Flaviviruses: Implications for Infection and Immunoprophylaxis","volume":"81","author":"FX Heinz","year":"2017","journal-title":"Microbiol Mol Biol Rev"},{"key":"pntd.0009425.ref024","first-page":"e00474","article-title":"Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response","volume":"91","author":"S Hou","year":"2017","journal-title":"J Virol"},{"key":"pntd.0009425.ref025","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.3390\/ijms20051101","article-title":"Advances in Zika Virus(-)Host Cell Interaction: Current Knowledge and Future Perspectives.","volume":"20","author":"JK Lee","year":"2019","journal-title":"Int J Mol Sci"},{"key":"pntd.0009425.ref026","doi-asserted-by":"crossref","first-page":"8880","DOI":"10.1128\/JVI.00354-15","article-title":"Biology of Zika Virus Infection in Human Skin Cells","volume":"89","author":"R Hamel","year":"2015","journal-title":"J Virol"},{"key":"pntd.0009425.ref027","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.jid.2018.07.038","article-title":"Insights into ZIKV-Mediated Innate Immune Responses in Human Dermal Fibroblasts and Epidermal Keratinocytes","volume":"139","author":"JA Kim","year":"2019","journal-title":"J Invest Dermatol"},{"key":"pntd.0009425.ref028","doi-asserted-by":"crossref","first-page":"3471","DOI":"10.1016\/j.celrep.2017.11.087","article-title":"Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication","volume":"21","author":"X Sun","year":"2017","journal-title":"Cell Rep"},{"key":"pntd.0009425.ref029","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1038\/s41564-017-0016-3","article-title":"Asian Zika virus strains target CD14(+) blood monocytes and induce M2-skewed immunosuppression during pregnancy.","volume":"2","author":"SS Foo","year":"2017","journal-title":"Nat Microbiol."},{"key":"pntd.0009425.ref030","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1038\/s41564-017-0035-0","article-title":"CD14(+)CD16(+) monocytes are the main target of Zika virus infection in peripheral blood mononuclear cells in a paediatric study in Nicaragua.","volume":"2","author":"D Michlmayr","year":"2017","journal-title":"Nat Microbiol"},{"key":"pntd.0009425.ref031","doi-asserted-by":"crossref","first-page":"43","DOI":"10.5858\/arpa.2016-0401-OA","article-title":"Placental Pathology of Zika Virus: Viral Infection of the Placenta Induces Villous Stromal Macrophage (Hofbauer Cell) Proliferation and Hyperplasia.","volume":"141","author":"AZ Rosenberg","year":"2017","journal-title":"Arch Pathol Lab Med"},{"key":"pntd.0009425.ref032","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.stem.2016.03.012","article-title":"Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells.","volume":"18","author":"TJ Nowakowski","year":"2016","journal-title":"Cell Stem Cell"},{"key":"pntd.0009425.ref033","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.celrep.2016.12.045","article-title":"Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses","volume":"18","author":"L Meertens","year":"2017","journal-title":"Cell Rep"},{"key":"pntd.0009425.ref034","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1097\/PAI.0000000000000580","article-title":"Cellular Targets and Receptor of Sexual Transmission of Zika Virus.","volume":"25","author":"O Bagasra","year":"2017","journal-title":"Appl Immunohistochem Mol Morphol"},{"key":"pntd.0009425.ref035","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1073\/pnas.1620558114","article-title":"AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses","volume":"114","author":"AS Richard","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pntd.0009425.ref036","doi-asserted-by":"crossref","first-page":"e13","DOI":"10.1038\/emi.2016.141","article-title":"Zika virus genome biology and molecular pathogenesis","volume":"6","author":"A Wang","year":"2017","journal-title":"Emerg Microbes Infect"},{"key":"pntd.0009425.ref037","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1089\/dna.2016.3404","article-title":"Mechanisms of Zika Virus Infection and Neuropathogenesis","volume":"35","author":"D Olagnier","year":"2016","journal-title":"DNA Cell Biol"},{"key":"pntd.0009425.ref038","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.meegid.2019.01.018","article-title":"ZIKA virus entry mechanisms in human cells","volume":"69","author":"A Agrelli","year":"2019","journal-title":"Infect Genet Evol"},{"key":"pntd.0009425.ref039","doi-asserted-by":"crossref","first-page":"e13302","DOI":"10.1111\/cmi.13302","article-title":"Valosin-containing protein ATPase activity regulates the morphogenesis of Zika virus replication organelles and virus-induced cell death","volume":"23","author":"A Anton","year":"2021","journal-title":"Cell Microbiol"},{"key":"pntd.0009425.ref040","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1101\/gr.082701.108","article-title":"Most mammalian mRNAs are conserved targets of microRNAs","volume":"19","author":"RC Friedman","year":"2009","journal-title":"Genome Res"},{"key":"pntd.0009425.ref041","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.bioeng.2006.01.002","article-title":"RNA interference in cancer","volume":"23","author":"AL Gartel","year":"2006","journal-title":"Biomol Eng"},{"key":"pntd.0009425.ref042","first-page":"313","article-title":"RNA interference and its role in cancer therapy","volume":"4","author":"B Mansoori","year":"2014","journal-title":"Adv Pharm Bull"},{"key":"pntd.0009425.ref043","doi-asserted-by":"crossref","first-page":"12934","DOI":"10.1128\/JVI.01179-14","article-title":"Viruses and RNA interference: issues and controversies","volume":"88","author":"BR Cullen","year":"2014","journal-title":"J Virol"},{"key":"pntd.0009425.ref044","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1111\/apha.12681","article-title":"MicroRNAs in metabolism","volume":"219","author":"S Vienberg","year":"2017","journal-title":"Acta Physiol (Oxf)."},{"key":"pntd.0009425.ref045","doi-asserted-by":"crossref","first-page":"824","DOI":"10.3389\/fmicb.2017.00824","article-title":"Viruses and miRNAs: More Friends than Foes.","volume":"8","author":"P Bruscella","year":"2017","journal-title":"Front Microbiol."},{"key":"pntd.0009425.ref046","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1755-8417-2-7","article-title":"microRNAs and genetic diseases","volume":"2","author":"N Meola","year":"2009","journal-title":"Pathogenetics"},{"key":"pntd.0009425.ref047","doi-asserted-by":"crossref","first-page":"297","DOI":"10.3390\/v9100297","article-title":"MicroRNA and mRNA Dysregulation in Astrocytes Infected with Zika Virus.","volume":"9","author":"RA Kozak","year":"2017","journal-title":"Viruses"},{"key":"pntd.0009425.ref048","doi-asserted-by":"crossref","first-page":"162","DOI":"10.3390\/v11020162","article-title":"Integrated MicroRNA and mRNA Profiling in Zika Virus-Infected Neurons.","volume":"11","author":"F Azouz","year":"2019","journal-title":"Viruses"},{"key":"pntd.0009425.ref049","doi-asserted-by":"crossref","first-page":"3618","DOI":"10.1016\/j.celrep.2019.05.059","article-title":"Genome-wide Integrative Analysis of Zika-Virus-Infected Neuronal Stem Cells Reveals Roles for MicroRNAs in Cell Cycle and Stemness.","volume":"27","author":"JW Dang","year":"2019","journal-title":"Cell Rep"},{"key":"pntd.0009425.ref050","doi-asserted-by":"crossref","first-page":"53","DOI":"10.3390\/v10020053","article-title":"Higher Cytopathic Effects of a Zika Virus Brazilian Isolate from Bahia Compared to a Canadian-Imported Thai Strain.","volume":"10","author":"SP Alpuche-Lazcano","year":"2018","journal-title":"Viruses"},{"key":"pntd.0009425.ref051","doi-asserted-by":"crossref","first-page":"728","DOI":"10.3390\/v10120728","article-title":"Contemporary Zika Virus Isolates Induce More dsRNA and Produce More Negative-Strand Intermediate in Human Astrocytoma Cells.","volume":"10","author":"TR Barnard","year":"2018","journal-title":"Viruses"},{"key":"pntd.0009425.ref052","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.3389\/fimmu.2017.01016","article-title":"Zika Virus Promotes Neuronal Cell Death in a Non-Cell Autonomous Manner by Triggering the Release of Neurotoxic Factors.","volume":"8","author":"IG Olmo","year":"2017","journal-title":"Front Immunol"},{"key":"pntd.0009425.ref053","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00430-014-0334-5","article-title":"Subversion of early innate antiviral responses during antibody-dependent enhancement of Dengue virus infection induces severe disease in immunocompetent mice","volume":"203","author":"VV Costa","year":"2014","journal-title":"Med Microbiol Immunol"},{"key":"pntd.0009425.ref054","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/1742-4690-10-96","article-title":"The PKR activator, PACT, becomes a PKR inhibitor during HIV-1 replication.","volume":"10","author":"G Clerzius","year":"2013","journal-title":"Retrovirology"},{"key":"pntd.0009425.ref055","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.omtn.2019.10.011","article-title":"A U1i RNA that Enhances HIV-1 RNA Splicing with an Elongated Recognition Domain Is an Optimal Candidate for Combination HIV-1 Gene Therapy.","volume":"18","author":"O Del Corpo","year":"2019","journal-title":"Mol Ther Nucleic Acids"},{"key":"pntd.0009425.ref056","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.celrep.2019.09.087","article-title":"NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor.","volume":"29","author":"M Bury","year":"2019","journal-title":"Cell Rep."},{"key":"pntd.0009425.ref057","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1111\/jcmm.14136","article-title":"Regulation of CXCL1 chemokine and CSF3 cytokine levels in myometrial cells by the MAFF transcription factor","volume":"23","author":"J Saliba","year":"2019","journal-title":"J Cell Mol Med"},{"key":"pntd.0009425.ref058","doi-asserted-by":"crossref","first-page":"e0156289","DOI":"10.1371\/journal.pone.0156289","article-title":"Stability of Reference Genes for Messenger RNA Quantification by Real-Time PCR in Mouse Dextran Sodium Sulfate Experimental Colitis.","volume":"11","author":"N Eissa","year":"2016","journal-title":"PLoS One"},{"key":"pntd.0009425.ref059","doi-asserted-by":"crossref","first-page":"e0194206","DOI":"10.1371\/journal.pone.0194206","article-title":"Tis21-gene therapy inhibits medulloblastoma growth in a murine allograft model.","volume":"13","author":"D Presutti","year":"2018","journal-title":"PLoS One"},{"key":"pntd.0009425.ref060","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1039\/C5MB00663E","article-title":"ReactomePA: an R\/Bioconductor package for reactome pathway analysis and visualization.","volume":"12","author":"G Yu","year":"2016","journal-title":"Mol Biosyst"},{"key":"pntd.0009425.ref061","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"G Yu","year":"2012","journal-title":"Omics"},{"key":"pntd.0009425.ref062","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-24277-4","volume-title":"ggplot2: Elegant Graphics for Data Analysis.","author":"H Wickham","year":"2016","edition":"2"},{"key":"pntd.0009425.ref063","unstructured":"Kolde R. pheatmap: Pretty heatmaps [Software] 2019. Available from: https:\/\/CRAN.R-project.org\/package=pheatmap."},{"key":"pntd.0009425.ref064","doi-asserted-by":"crossref","first-page":"D146","DOI":"10.1093\/nar\/gku1104","article-title":"miRDB: an online resource for microRNA target prediction and functional annotations","volume":"43","author":"N Wong","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"pntd.0009425.ref065","doi-asserted-by":"crossref","first-page":"05005","DOI":"10.7554\/eLife.05005","article-title":"Predicting effective microRNA target sites in mammalian mRNAs.","volume":"4","author":"V Agarwal","year":"2015","journal-title":"Elife"},{"key":"pntd.0009425.ref066","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1038\/nsmb.2115","article-title":"Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs","volume":"18","author":"DM Garcia","year":"2011","journal-title":"Nat Struct Mol Biol"},{"key":"pntd.0009425.ref067","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.molcel.2007.06.017","article-title":"MicroRNA targeting specificity in mammals: determinants beyond seed pairing","volume":"27","author":"A Grimson","year":"2007","journal-title":"Mol Cell"},{"key":"pntd.0009425.ref068","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cell.2004.12.035","article-title":"Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets","volume":"120","author":"BP Lewis","year":"2005","journal-title":"Cell"},{"key":"pntd.0009425.ref069","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.tins.2016.02.003","article-title":"Npas4: Linking Neuronal Activity to Memory","volume":"39","author":"X Sun","year":"2016","journal-title":"Trends Neurosci"},{"key":"pntd.0009425.ref070","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jsbmb.2015.04.016","article-title":"Nuclear receptor 4A (NR4A) family\u2014orphans no more.","volume":"157","author":"S Safe","year":"2016","journal-title":"J Steroid Biochem Mol Biol"},{"key":"pntd.0009425.ref071","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1038\/nature07319","article-title":"Activity-dependent regulation of inhibitory synapse development by Npas4","volume":"455","author":"Y Lin","year":"2008","journal-title":"Nature"},{"key":"pntd.0009425.ref072","doi-asserted-by":"crossref","first-page":"146","DOI":"10.2174\/1566524015666150303003028","article-title":"Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders","volume":"15","author":"R Gao","year":"2015","journal-title":"Curr Mol Med"},{"key":"pntd.0009425.ref073","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.bbr.2014.12.044","article-title":"Effects of Npas4 deficiency on anxiety, depression-like, cognition and sociability behaviour","volume":"281","author":"EJ Jaehne","year":"2015","journal-title":"Behav Brain Res"},{"key":"pntd.0009425.ref074","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3389\/fnana.2015.00145","article-title":"Expression of Npas4 mRNA in Telencephalic Areas of Adult and Postnatal Mouse Brain.","volume":"9","author":"JC Damborsky","year":"2015","journal-title":"Front Neuroanat"},{"key":"pntd.0009425.ref075","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/scrt453","article-title":"A reduction in Npas4 expression results in delayed neural differentiation of mouse embryonic stem cells","volume":"5","author":"TS Klaric","year":"2014","journal-title":"Stem Cell Res Ther"},{"key":"pntd.0009425.ref076","doi-asserted-by":"crossref","first-page":"e12448","DOI":"10.1111\/gbb.12448","article-title":"Npas4 deficiency and prenatal stress interact to affect social recognition in mice","volume":"17","author":"K Heslin","year":"2018","journal-title":"Genes Brain Behav"},{"key":"pntd.0009425.ref077","doi-asserted-by":"crossref","first-page":"603373","DOI":"10.3389\/fnins.2020.603373","article-title":"Essential Functions of the Transcription Factor Npas4 in Neural Circuit Development, Plasticity, and Diseases.","volume":"14","author":"J Fu","year":"2020","journal-title":"Front Neurosci."},{"key":"pntd.0009425.ref078","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1042\/BST0390688","article-title":"Inflammation: a role for NR4A orphan nuclear receptors?","volume":"39","author":"JP McMorrow","year":"2011","journal-title":"Biochem Soc Trans"},{"key":"pntd.0009425.ref079","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1084\/jem.20021842","article-title":"Orphan nuclear receptor Nur77 is involved in caspase-independent macrophage cell death","volume":"197","author":"SO Kim","year":"2003","journal-title":"J Exp Med"},{"key":"pntd.0009425.ref080","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1084\/jem.20080101","article-title":"During negative selection, Nur77 family proteins translocate to mitochondria where they associate with Bcl-2 and expose its proapoptotic BH3 domain","volume":"205","author":"J Thompson","year":"2008","journal-title":"J Exp Med"},{"key":"pntd.0009425.ref081","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/ng1066","article-title":"Mutations in NR4A2 associated with familial Parkinson disease","volume":"33","author":"WD Le","year":"2003","journal-title":"Nat Genet"},{"key":"pntd.0009425.ref082","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1126\/science.276.5310.248","article-title":"Dopamine neuron agenesis in Nurr1-deficient mice","volume":"276","author":"RH Zetterstrom","year":"1997","journal-title":"Science"},{"key":"pntd.0009425.ref083","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.0105-2896.2006.00427.x","article-title":"Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease","volume":"212","author":"S Sakaguchi","year":"2006","journal-title":"Immunol Rev"},{"key":"pntd.0009425.ref084","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/ncomms1272","article-title":"The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells.","volume":"2","author":"T Sekiya","year":"2011","journal-title":"Nat Commun."},{"key":"pntd.0009425.ref085","doi-asserted-by":"crossref","first-page":"9070","DOI":"10.1128\/MCB.24.20.9070-9078.2004","article-title":"nor-1 regulates hippocampal axon guidance, pyramidal cell survival, and seizure susceptibility","volume":"24","author":"T Ponnio","year":"2004","journal-title":"Mol Cell Biol"},{"key":"pntd.0009425.ref086","doi-asserted-by":"crossref","first-page":"47104","DOI":"10.1074\/jbc.M307496200","article-title":"The orphan steroid receptor Nur77 family member Nor-1 is essential for early mouse embryogenesis","volume":"278","author":"RA DeYoung","year":"2003","journal-title":"J Biol Chem"},{"key":"pntd.0009425.ref087","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1111\/jcmm.14804","article-title":"The pro-inflammatory effect of NR4A3 in osteoarthritis","volume":"24","author":"C Ma","year":"2020","journal-title":"J Cell Mol Med"},{"key":"pntd.0009425.ref088","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/sj.mp.4001379","article-title":"Neuronal expression of GFAP in patients with Alzheimer pathology and identification of novel GFAP splice forms","volume":"8","author":"EM Hol","year":"2003","journal-title":"Mol Psychiatry"},{"key":"pntd.0009425.ref089","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.neuroscience.2009.12.026","article-title":"Glial fibrillary acidic protein-expressing neural progenitors give rise to immature neurons via early intermediate progenitors expressing both glial fibrillary acidic protein and neuronal markers in the adult hippocampus","volume":"166","author":"Y Liu","year":"2010","journal-title":"Neuroscience"},{"key":"pntd.0009425.ref090","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1242\/dev.041632","article-title":"GFAPdelta in radial glia and subventricular zone progenitors in the developing human cortex","volume":"137","author":"J Middeldorp","year":"2010","journal-title":"Development"},{"key":"pntd.0009425.ref091","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1002\/bdrc.20070","article-title":"MicroRNAs and cell differentiation in mammalian development","volume":"78","author":"L Song","year":"2006","journal-title":"Birth Defects Res C Embryo Today"},{"key":"pntd.0009425.ref092","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/sj.bjc.6603023","article-title":"MicroRNAs in cell proliferation, cell death, and tumorigenesis","volume":"94","author":"HW Hwang","year":"2006","journal-title":"Br J Cancer"},{"key":"pntd.0009425.ref093","first-page":"161","article-title":"The Role of MicroRNAs in Human Diseases.","volume":"2","author":"AM Ardekani","year":"2010","journal-title":"Avicenna J Med Biotechnol."},{"key":"pntd.0009425.ref094","doi-asserted-by":"crossref","DOI":"10.1093\/hmg\/ddi101","article-title":"Small regulatory RNAs in mammals","volume":"14","author":"JS Mattick","year":"2005","journal-title":"Hum Mol Genet"},{"key":"pntd.0009425.ref095","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.conb.2017.02.014","article-title":"miRNAs in synapse development and synaptic plasticity","volume":"45","author":"Z Hu","year":"2017","journal-title":"Curr Opin Neurobiol"},{"key":"pntd.0009425.ref096","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.mad.2017.01.007","article-title":"MicroRNAs in brain aging","volume":"168","author":"CP Danka Mohammed","year":"2017","journal-title":"Mech Ageing Dev"},{"key":"pntd.0009425.ref097","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1242\/dev.144337","article-title":"MicroRNAs in neural development: from master regulators to fine-tuners","volume":"144","author":"M Rajman","year":"2017","journal-title":"Development"},{"key":"pntd.0009425.ref098","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1074\/jbc.RA119.007389","article-title":"The microRNAs let-7 and miR-9 down-regulate the axon-guidance genes Ntn1 and Dcc during peripheral nerve regeneration","volume":"294","author":"X Wang","year":"2019","journal-title":"J Biol Chem"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0009425","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0009425","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T00:09:02Z","timestamp":1623370142000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0009425"}},"subtitle":[],"editor":[{"given":"Joao Trindade","family":"Marques","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,5,28]]},"references-count":98,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0009425","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0009425","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,28]]}}}