{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T12:36:56Z","timestamp":1780490216601,"version":"3.54.1"},"reference-count":38,"publisher":"American Society for Microbiology","issue":"17","license":[{"start":{"date-parts":[[2017,9,1]],"date-time":"2017-09-01T00:00:00Z","timestamp":1504224000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2015R1A2A2A01005687"],"award-info":[{"award-number":["2015R1A2A2A01005687"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Despite the high incidence of severe defects in the central nervous system caused by human cytomegalovirus (HCMV) congenital infection, the mechanism of HCMV neuropathogenesis and the roles of individual viral genes have not yet been fully determined. In this study, we show that the immediate-early 2 (IE2) protein may play a key role in HCMV-caused neurodevelopmental disorders. IE2-transduced neural progenitor cells gave rise to neurospheres with a lower frequency and produced smaller neurospheres than control cells\n            <jats:italic>in vitro<\/jats:italic>\n            , indicating reduction of self-renewal and expansion of neural progenitors by IE2. At 2 days after\n            <jats:italic>in utero<\/jats:italic>\n            electroporation into the ventricle of the developing brain, a dramatically lower percentage of IE2-expressing cells was detected in the ventricular zone (VZ) and cortical plate (CP) compared to control cells, suggesting that IE2 concurrently dysregulates neural stem cell maintenance in the VZ and neuronal migration to the CP. In addition, most IE2\n            <jats:sup>+<\/jats:sup>\n            cells in the lower intermediate zone either showed multipolar morphology with short neurites or possessed nonradially oriented processes, whereas control cells had long, radially oriented monopolar or bipolar neurites. IE2\n            <jats:sup>+<\/jats:sup>\n            callosal axons also failed to cross the midline to form the corpus callosum. Furthermore, we provide molecular evidence that the cell cycle arrest and DNA binding activities of IE2 appear to be responsible for the increased neural stem cell exit from the VZ and cortical migrational defects, respectively. Collectively, our results demonstrate that IE2 disrupts the orderly process of brain development in a stepwise manner to further our understanding of neurodevelopmental HCMV pathogenesis.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            HCMV brain pathogenesis has been studied in limited experimental settings, such as\n            <jats:italic>in vitro<\/jats:italic>\n            HCMV infection of neural progenitor cells or\n            <jats:italic>in vivo<\/jats:italic>\n            murine CMV infection of the mouse brain. Here, we show that IE2 is a pivotal factor that contributes to HCMV-induced abnormalities in the context of the embryonic brain using an\n            <jats:italic>in utero<\/jats:italic>\n            gene transfer tool. Surprisingly, IE2, but not HCMV IE1 or murine CMV ie3, interferes pleiotropically with key neurodevelopmental processes, including neural stem cell regulation, proper positioning of migrating neurons, and the callosal axon projections important for communication between the hemispheres. Our data suggest that the wide spectrum of clinical outcomes, ranging from mental retardation to microcephaly, caused by congenital HCMV infection can be sufficiently explained in terms of IE2 action alone.\n          <\/jats:p>","DOI":"10.1128\/jvi.00799-17","type":"journal-article","created":{"date-parts":[[2017,6,15]],"date-time":"2017-06-15T00:40:24Z","timestamp":1497487224000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":27,"title":["Human Cytomegalovirus IE2 Protein Disturbs Brain Development by the Dysregulation of Neural Stem Cell Maintenance and the Polarization of Migrating Neurons"],"prefix":"10.1128","volume":"91","author":[{"given":"Dasol","family":"Han","sequence":"first","affiliation":[{"name":"College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Hyun","family":"Byun","sequence":"additional","affiliation":[{"name":"College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juwan","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mookwang","family":"Kwon","sequence":"additional","affiliation":[{"name":"College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J.","family":"Pleasure","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Hyun","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2361-9039","authenticated-orcid":false,"given":"Keejung","family":"Yoon","sequence":"additional","affiliation":[{"name":"College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.4437"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/13.2.315"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2007.09.004"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.spid.2004.09.011"},{"key":"e_1_3_2_6_2","first-page":"703","article-title":"Congenital cytomegalovirus infection of the brain: imaging analysis and embryologic considerations","volume":"15","author":"Barkovich AJ","year":"1994","unstructured":"Barkovich AJ Lindan CE . 1994. 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