The suppression of maternal-fetal leukemia inhibitory factor signal relay pathway by maternal immune activation impairs brain development in mice
Recent studies in rodents suggest that maternal immune activation (MIA) by viral infection is associated with schizophrenia and autism in offspring. Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucida...
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| creator | Tsukada, Tsuyoshi Simamura, Eriko Shimada, Hiroki Arai, Takuma Higashi, Nobuaki Akai, Takuya Iizuka, Hideaki Hatta, Toshihisa |
| description | Recent studies in rodents suggest that maternal immune activation (MIA) by viral infection is associated with schizophrenia and autism in offspring. Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucidated. Previously, we reported that the maternal leukemia inhibitory factor (LIF)-placental ACTH-fetal LIF signaling relay pathway (maternal-fetal LIF signal relay) promotes neurogenesis of fetal cerebrum in rats. Here we report that the maternal-fetal LIF signal relay in mice is suppressed by injection of polyriboinosinic-polyribocytidylic acid into dams, which induces MIA at 12.5 days post-coitum. Maternal IL-6 levels and gene expression of placental suppressor of cytokine signaling 3 (Socs3) increased according to the severity of MIA and gene expression of placental Socs3 correlated with maternal IL-6 levels. Furthermore, we show that MIA causes reduction of LIF level in the fetal cerebrospinal fluid, resulting in the decreased neurogenesis in the cerebrum. These findings suggest that maternal IL-6 interferes the maternal-fetal LIF signal relay by inducing SOCS3 in the placenta and leads to decreased neurogenesis. |
| doi_str_mv | 10.1371/journal.pone.0129011 |
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Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucidated. Previously, we reported that the maternal leukemia inhibitory factor (LIF)-placental ACTH-fetal LIF signaling relay pathway (maternal-fetal LIF signal relay) promotes neurogenesis of fetal cerebrum in rats. Here we report that the maternal-fetal LIF signal relay in mice is suppressed by injection of polyriboinosinic-polyribocytidylic acid into dams, which induces MIA at 12.5 days post-coitum. Maternal IL-6 levels and gene expression of placental suppressor of cytokine signaling 3 (Socs3) increased according to the severity of MIA and gene expression of placental Socs3 correlated with maternal IL-6 levels. Furthermore, we show that MIA causes reduction of LIF level in the fetal cerebrospinal fluid, resulting in the decreased neurogenesis in the cerebrum. These findings suggest that maternal IL-6 interferes the maternal-fetal LIF signal relay by inducing SOCS3 in the placenta and leads to decreased neurogenesis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0129011</identifier><identifier>PMID: 26043040</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Adrenocorticotropic hormone ; Adrenocorticotropic Hormone - metabolism ; Animals ; Autism ; Brain ; Brain - embryology ; Brain - metabolism ; Cell division ; Cerebrospinal fluid ; Cerebrum ; Corticotropin ; Cytokine Receptor gp130 - metabolism ; Cytokines ; Disease susceptibility ; Embryos ; Female ; Fetus - metabolism ; Fetuses ; Fluids ; Gene expression ; Gene Expression Regulation ; Health aspects ; Immune response ; Immunity ; Infection ; Infections ; Interleukin 6 ; Interleukin-6 - metabolism ; Janus Kinases - metabolism ; Laboratory animals ; Leukemia ; Leukemia inhibitory factor ; Leukemia Inhibitory Factor - metabolism ; Mental disorders ; Mice, Inbred C57BL ; Neurogenesis ; Neurosurgery ; Offspring ; Placenta ; Placenta - metabolism ; Pregnancy ; Relay ; Rodents ; Schizophrenia ; Signal Transduction ; Signaling ; SOCS-3 protein ; STAT3 Transcription Factor - metabolism ; Viral infections</subject><ispartof>PloS one, 2015-06, Vol.10 (6), p.e0129011-e0129011</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Tsukada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Tsukada et al 2015 Tsukada et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-c439ebc02df7b8a64c6774e0472ff106877b7624111a2e2b5ea7064d08975f883</citedby><cites>FETCH-LOGICAL-c758t-c439ebc02df7b8a64c6774e0472ff106877b7624111a2e2b5ea7064d08975f883</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456156/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456156/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26043040$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tsukada, Tsuyoshi</creatorcontrib><creatorcontrib>Simamura, Eriko</creatorcontrib><creatorcontrib>Shimada, Hiroki</creatorcontrib><creatorcontrib>Arai, Takuma</creatorcontrib><creatorcontrib>Higashi, Nobuaki</creatorcontrib><creatorcontrib>Akai, Takuya</creatorcontrib><creatorcontrib>Iizuka, Hideaki</creatorcontrib><creatorcontrib>Hatta, Toshihisa</creatorcontrib><title>The suppression of maternal-fetal leukemia inhibitory factor signal relay pathway by maternal immune activation impairs brain development in mice</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Recent studies in rodents suggest that maternal immune activation (MIA) by viral infection is associated with schizophrenia and autism in offspring. Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucidated. Previously, we reported that the maternal leukemia inhibitory factor (LIF)-placental ACTH-fetal LIF signaling relay pathway (maternal-fetal LIF signal relay) promotes neurogenesis of fetal cerebrum in rats. Here we report that the maternal-fetal LIF signal relay in mice is suppressed by injection of polyriboinosinic-polyribocytidylic acid into dams, which induces MIA at 12.5 days post-coitum. Maternal IL-6 levels and gene expression of placental suppressor of cytokine signaling 3 (Socs3) increased according to the severity of MIA and gene expression of placental Socs3 correlated with maternal IL-6 levels. Furthermore, we show that MIA causes reduction of LIF level in the fetal cerebrospinal fluid, resulting in the decreased neurogenesis in the cerebrum. These findings suggest that maternal IL-6 interferes the maternal-fetal LIF signal relay by inducing SOCS3 in the placenta and leads to decreased neurogenesis.</description><subject>Activation</subject><subject>Adrenocorticotropic hormone</subject><subject>Adrenocorticotropic Hormone - metabolism</subject><subject>Animals</subject><subject>Autism</subject><subject>Brain</subject><subject>Brain - embryology</subject><subject>Brain - metabolism</subject><subject>Cell division</subject><subject>Cerebrospinal fluid</subject><subject>Cerebrum</subject><subject>Corticotropin</subject><subject>Cytokine Receptor gp130 - metabolism</subject><subject>Cytokines</subject><subject>Disease susceptibility</subject><subject>Embryos</subject><subject>Female</subject><subject>Fetus - metabolism</subject><subject>Fetuses</subject><subject>Fluids</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Health aspects</subject><subject>Immune response</subject><subject>Immunity</subject><subject>Infection</subject><subject>Infections</subject><subject>Interleukin 6</subject><subject>Interleukin-6 - metabolism</subject><subject>Janus Kinases - metabolism</subject><subject>Laboratory animals</subject><subject>Leukemia</subject><subject>Leukemia inhibitory factor</subject><subject>Leukemia Inhibitory Factor - metabolism</subject><subject>Mental disorders</subject><subject>Mice, Inbred C57BL</subject><subject>Neurogenesis</subject><subject>Neurosurgery</subject><subject>Offspring</subject><subject>Placenta</subject><subject>Placenta - metabolism</subject><subject>Pregnancy</subject><subject>Relay</subject><subject>Rodents</subject><subject>Schizophrenia</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>SOCS-3 protein</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Viral infections</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk81u1DAQxyMEoqXwBggsISE47GI7jp1ckKqKj5UqVYLC1XKcya4XJ07tpLCPwRvjsOlqg3pAPow_fvO3ZzyTJM8JXpJUkHdbN_hW2WXnWlhiQgtMyIPklBQpXXCK04dH85PkSQhbjLM05_xxckI5Zilm-DT5fb0BFIau8xCCcS1yNWpUD6P0ooZeWWRh-AGNUci0G1Oa3vkdqpWOFgWzjhzyYNUOdarf_Iy23B0UkGmaoQUUaXOr-lHfNJ0yPqDSK9OiCm7Buq6Bto_yqDEaniaPamUDPJvsWfLt44fri8-Ly6tPq4vzy4UWWd4vNEsLKDWmVS3KXHGmuRAMMBO0rgnmuRCl4JQRQhQFWmagBOaswnkhsjrP07Pk5V63sy7IKZtBEp7zyImCRmK1JyqntrLzplF-J50y8u-G82upfG-0BZlllJWapDQmlfE0LUrBsqKKy5QCL0TUej_dNpQNVDoG7JWdic5PWrORa3crGcs4yXgUeDMJeHczQOhlY4IGa1ULbti_uyhylmURffUPen90E7VWMQDT1i7eq0dRec4I57Gg2Pju5T1UHFUsCR1LrzZxf-bwduYQmR5-9Ws1hCBXX7_8P3v1fc6-PmI3oGy_Cc4OY1GFOcj2oPYuBA_1IckEy7Fz7rIhx86RU-dEtxfHH3RwumuV9A_L6xRi</recordid><startdate>20150604</startdate><enddate>20150604</enddate><creator>Tsukada, Tsuyoshi</creator><creator>Simamura, Eriko</creator><creator>Shimada, Hiroki</creator><creator>Arai, Takuma</creator><creator>Higashi, Nobuaki</creator><creator>Akai, Takuya</creator><creator>Iizuka, Hideaki</creator><creator>Hatta, Toshihisa</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150604</creationdate><title>The suppression of maternal-fetal leukemia inhibitory factor signal relay pathway by maternal immune activation impairs brain development in mice</title><author>Tsukada, Tsuyoshi ; Simamura, Eriko ; Shimada, Hiroki ; Arai, Takuma ; Higashi, Nobuaki ; Akai, Takuya ; Iizuka, Hideaki ; Hatta, Toshihisa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-c439ebc02df7b8a64c6774e0472ff106877b7624111a2e2b5ea7064d08975f883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Activation</topic><topic>Adrenocorticotropic hormone</topic><topic>Adrenocorticotropic Hormone - metabolism</topic><topic>Animals</topic><topic>Autism</topic><topic>Brain</topic><topic>Brain - embryology</topic><topic>Brain - metabolism</topic><topic>Cell division</topic><topic>Cerebrospinal fluid</topic><topic>Cerebrum</topic><topic>Corticotropin</topic><topic>Cytokine Receptor gp130 - metabolism</topic><topic>Cytokines</topic><topic>Disease susceptibility</topic><topic>Embryos</topic><topic>Female</topic><topic>Fetus - metabolism</topic><topic>Fetuses</topic><topic>Fluids</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Health aspects</topic><topic>Immune response</topic><topic>Immunity</topic><topic>Infection</topic><topic>Infections</topic><topic>Interleukin 6</topic><topic>Interleukin-6 - metabolism</topic><topic>Janus Kinases - metabolism</topic><topic>Laboratory animals</topic><topic>Leukemia</topic><topic>Leukemia inhibitory factor</topic><topic>Leukemia Inhibitory Factor - metabolism</topic><topic>Mental disorders</topic><topic>Mice, Inbred C57BL</topic><topic>Neurogenesis</topic><topic>Neurosurgery</topic><topic>Offspring</topic><topic>Placenta</topic><topic>Placenta - 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Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucidated. Previously, we reported that the maternal leukemia inhibitory factor (LIF)-placental ACTH-fetal LIF signaling relay pathway (maternal-fetal LIF signal relay) promotes neurogenesis of fetal cerebrum in rats. Here we report that the maternal-fetal LIF signal relay in mice is suppressed by injection of polyriboinosinic-polyribocytidylic acid into dams, which induces MIA at 12.5 days post-coitum. Maternal IL-6 levels and gene expression of placental suppressor of cytokine signaling 3 (Socs3) increased according to the severity of MIA and gene expression of placental Socs3 correlated with maternal IL-6 levels. Furthermore, we show that MIA causes reduction of LIF level in the fetal cerebrospinal fluid, resulting in the decreased neurogenesis in the cerebrum. These findings suggest that maternal IL-6 interferes the maternal-fetal LIF signal relay by inducing SOCS3 in the placenta and leads to decreased neurogenesis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26043040</pmid><doi>10.1371/journal.pone.0129011</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Activation Adrenocorticotropic hormone Adrenocorticotropic Hormone - metabolism Animals Autism Brain Brain - embryology Brain - metabolism Cell division Cerebrospinal fluid Cerebrum Corticotropin Cytokine Receptor gp130 - metabolism Cytokines Disease susceptibility Embryos Female Fetus - metabolism Fetuses Fluids Gene expression Gene Expression Regulation Health aspects Immune response Immunity Infection Infections Interleukin 6 Interleukin-6 - metabolism Janus Kinases - metabolism Laboratory animals Leukemia Leukemia inhibitory factor Leukemia Inhibitory Factor - metabolism Mental disorders Mice, Inbred C57BL Neurogenesis Neurosurgery Offspring Placenta Placenta - metabolism Pregnancy Relay Rodents Schizophrenia Signal Transduction Signaling SOCS-3 protein STAT3 Transcription Factor - metabolism Viral infections |
| title | The suppression of maternal-fetal leukemia inhibitory factor signal relay pathway by maternal immune activation impairs brain development in mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T13%3A19%3A57IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20suppression%20of%20maternal-fetal%20leukemia%20inhibitory%20factor%20signal%20relay%20pathway%20by%20maternal%20immune%20activation%20impairs%20brain%20development%20in%20mice&rft.jtitle=PloS%20one&rft.au=Tsukada,%20Tsuyoshi&rft.date=2015-06-04&rft.volume=10&rft.issue=6&rft.spage=e0129011&rft.epage=e0129011&rft.pages=e0129011-e0129011&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0129011&rft_dat=%3Cgale_plos_%3EA416629047%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1686064792&rft_id=info:pmid/26043040&rft_galeid=A416629047&rft_doaj_id=oai_doaj_org_article_5524bc13204046339b7459d20432e697&rfr_iscdi=true |