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Screening for genetic modulators in an LPS murine model of preterm birth revealed the upregulation of <jats:italic>Nr4a1<\/jats:italic>, an orphan nuclear transcription factor that is normally absent or limited in embryonic brains. Concurrently, <jats:italic>Nr4a1<\/jats:italic> was downregulated with magnesium sulfate (MgSO<jats:sub>4<\/jats:sub>) and betamethasone (BMTZ) treatments administered to LPS exposed dams. To understand the role of <jats:italic>Nr4a1<\/jats:italic> in perinatal brain injury, we compared the preterm neuroinflammatory response in <jats:italic>Nr4a1<\/jats:italic> knockout (KO) versus wild type (wt) mice. Key inflammatory factors <jats:italic>Il1b<\/jats:italic>, <jats:italic>Il6<\/jats:italic> and <jats:italic>Tnf<\/jats:italic>, and Iba1+ microglia were significantly lower in <jats:italic>Nr4a1<\/jats:italic> KO versus wt brains exposed to LPS in utero. Treatment with MgSO<jats:sub>4<\/jats:sub>\/BMTZ mitigated the neuroinflammatory process in wt but not <jats:italic>Nr4a1<\/jats:italic> KO brains. These results correspond with a reduction in cerebral hemorrhage in wt but not mutant embryos from dams given MgSO<jats:sub>4<\/jats:sub>\/BMTZ. Further analysis with <jats:italic>Nr4a1-GFP-Cre<\/jats:italic>\u2009\u00d7\u2009<jats:italic>tdTomato loxP<\/jats:italic> reporter mice revealed that the upregulation of <jats:italic>Nr4a1<\/jats:italic> with perinatal neuroinflammation occurs in the cerebral vasculature. Altogether, this study implicates <jats:italic>Nr4a1<\/jats:italic> in the developing vasculature as a potent mediator of neuroinflammatory brain injury that occurs with preterm birth. It is also possible that MgSO<jats:sub>4<\/jats:sub>\/BMTZ mitigates this process by direct or indirect inhibition of <jats:italic>Nr4a1<\/jats:italic>.<\/jats:p>","DOI":"10.1038\/s41419-019-2196-7","type":"journal-article","created":{"date-parts":[[2020,1,6]],"date-time":"2020-01-06T09:03:31Z","timestamp":1578301411000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The orphan nuclear receptor Nr4a1 mediates perinatal neuroinflammation in a murine model of preterm labor"],"prefix":"10.1038","volume":"11","author":[{"given":"Sarah M.","family":"Estrada","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew S.","family":"Thagard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary J.","family":"Dehart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer R.","family":"Damicis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth M.","family":"Dornisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle L.","family":"Ippolito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Burd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter G.","family":"Napolitano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Ieronimakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,6]]},"reference":[{"key":"2196_CR1","unstructured":"Martin, J. 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