{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T02:41:12Z","timestamp":1784601672622,"version":"3.55.0"},"reference-count":77,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T00:00:00Z","timestamp":1734912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS)","award":["17K07243"],"award-info":[{"award-number":["17K07243"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["21K06127"],"award-info":[{"award-number":["21K06127"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["23221010"],"award-info":[{"award-number":["23221010"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["16H02478"],"award-info":[{"award-number":["16H02478"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["20K20584"],"award-info":[{"award-number":["20K20584"]}]},{"name":"Nanken Kyoten Program, Medical Research Institute, Tokyo Medical and Dental University (TMDU)","award":["17K07243"],"award-info":[{"award-number":["17K07243"]}]},{"name":"Nanken Kyoten Program, Medical Research Institute, Tokyo Medical and Dental University (TMDU)","award":["21K06127"],"award-info":[{"award-number":["21K06127"]}]},{"name":"Nanken Kyoten Program, Medical Research Institute, Tokyo Medical and Dental University (TMDU)","award":["23221010"],"award-info":[{"award-number":["23221010"]}]},{"name":"Nanken Kyoten Program, Medical Research Institute, Tokyo Medical and Dental University (TMDU)","award":["16H02478"],"award-info":[{"award-number":["16H02478"]}]},{"name":"Nanken Kyoten Program, Medical Research Institute, Tokyo Medical and Dental University (TMDU)","award":["20K20584"],"award-info":[{"award-number":["20K20584"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Retrotransposon Gag-like 4 (RTL4), a gene acquired from a retrovirus, is a causative gene in autism spectrum disorder. Its knockout mice exhibit increased impulsivity, impaired short-term spatial memory, failure to adapt to novel environments, and delayed noradrenaline (NA) recovery in the frontal cortex. However, due to its very low expression in the brain, it remains unknown which brain cells express RTL4 and its dynamics in relation to NA. We addressed these issues using knock-in mice carrying endogenous Rtl4 fused to Venus, which encodes a fluorescent protein. The RTL4-Venus fusion protein was detected as a secreted protein in the midbrain, hypothalamus, hippocampus and amygdala in the postnatal brain. Its signal intensity was high during critical periods of neonatal adaptation to novel environments. It was upregulated by various stimuli, including isoproterenol administration, whereas it was decreased by anesthesia but was maintained by milnacipran administration, suggesting its highly sensitive response to stressors, possible dependence on the arousal state and involvement in the NA reuptake process. In vitro mixed glial culture experiments demonstrated that Rtl4 is a microglial gene and suggested that RTL4 secretion responds rapidly to isoproterenol. Microglial RTL4 plays an important role in the NA response and possibly in the development of the NAergic neuronal network in the brain.<\/jats:p>","DOI":"10.3390\/ijms252413738","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T09:13:38Z","timestamp":1734945218000},"page":"13738","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["RTL4, a Retrovirus-Derived Gene Implicated in Autism Spectrum Disorder, Is a Microglial Gene That Responds to Noradrenaline in the Postnatal Brain"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8458-6069","authenticated-orcid":false,"given":"Fumitoshi","family":"Ishino","sequence":"first","affiliation":[{"name":"Department of Epigenetics, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3983-3165","authenticated-orcid":false,"given":"Johbu","family":"Itoh","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayumi","family":"Matsuzawa","sequence":"additional","affiliation":[{"name":"Department of Epigenetics, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahito","family":"Irie","sequence":"additional","affiliation":[{"name":"Department of Epigenetics, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan"},{"name":"Faculty of Nursing, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Editing for Biomedical Research, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Hiraoka","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Editing for Biomedical Research, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan"},{"name":"Laboratory of Molecular Neuroscience, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanobu","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2566-9961","authenticated-orcid":false,"given":"Tomoko","family":"Kaneko-Ishino","sequence":"additional","affiliation":[{"name":"Faculty of Nursing, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1006\/geno.2001.6494","article-title":"A retrotransposon-derived gene, PEG10, is a novel imprinted gene located on human chromosome 7q21","volume":"73","author":"Ono","year":"2001","journal-title":"Genomics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1101\/gr.172701","article-title":"Human-ovine comparative sequencing of a 250-kb imprinted domain encompassing the callipyge (clpg) locus and identification of six imprinted transcripts: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8","volume":"11","author":"Charlier","year":"2001","journal-title":"Genome Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.gene.2004.11.022","article-title":"Transposable elements as a source of genetic innovation: Expression and evolution of a family of retrotransposon-derived neogenes in mammals","volume":"345","author":"Brandt","year":"2005","journal-title":"Gene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00239-004-0332-0","article-title":"A small family of sushi-class retrotransposon-derived genes in mammals and their relation to genomic imprinting","volume":"61","author":"Youngson","year":"2005","journal-title":"J. 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