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Melanoma antigen gene-D1 (MAGE-D1) interacts with RING E3 ubiquitin ligase and is implicated in protein degradation. MAGE-D1 may thus play an important role in the CNS via ubiquitylation. Here, we clarified a novel role of MAGE-D1 in emotional functions, namely its modulation of ubiquitylation to the serotonin transporter (SERT). The MAGE-D1 knock-out and knockdown by small interfering RNA (siRNA) in the prefrontal cortex showed depression-like behavior, such as a decrease in exploratory behavior in both the home cage and novel apparatus, a decrease in social interaction, increased immobility time during forced swimming and tail suspension, and a decrease in sucrose preference without any anxiety, or cognitive or motor dysfunction. Acute and chronic (28 d) administration of sertraline (10 mg\/kg) and imipramine (20 mg\/kg) reversed all or part of depression-like behavior in knock-out mice. In these mice, the serotonergic function in the prefrontal cortex and hippocampus was hypoactive, accompanied by hyperexpression of SERT attributable to a decrease in ubiquitylation. Furthermore, MAGE-D1 binds to SERT via the necdin homology domain. MAGE-D1 overexpression in cells resulted in a decrease in serotonin uptake activity and the protein level of SERT but an increase in ubiquitylated SERT. Together, the present findings suggest a novel role for MAGE-D1 in depressive behaviors: modulating SERT ubiquitylation.<\/jats:p>","DOI":"10.1523\/jneurosci.6458-11.2012","type":"journal-article","created":{"date-parts":[[2012,3,28]],"date-time":"2012-03-28T16:39:04Z","timestamp":1332952744000},"page":"4562-4580","source":"Crossref","is-referenced-by-count":82,"title":["MAGE-D1 Regulates Expression of Depression-Like Behavior through Serotonin Transporter Ubiquitylation"],"prefix":"10.1523","volume":"32","author":[{"given":"Akihiro","family":"Mouri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiharu","family":"Sogawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeo","family":"Kitayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayoshi","family":"Mamiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Miyamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyofumi","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukihiro","family":"Noda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshitaka","family":"Nabeshima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2012,3,28]]},"reference":[{"key":"2023041303554018000_32.13.4562.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1101678"},{"key":"2023041303554018000_32.13.4562.2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.10160"},{"key":"2023041303554018000_32.13.4562.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(98)00390-2"},{"key":"2023041303554018000_32.13.4562.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0406458102"},{"key":"2023041303554018000_32.13.4562.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2003.08.004"},{"key":"2023041303554018000_32.13.4562.6","doi-asserted-by":"publisher","DOI":"10.1038\/nn1964"},{"key":"2023041303554018000_32.13.4562.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2007.03.016"},{"key":"2023041303554018000_32.13.4562.8","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(98)01258-X"},{"key":"2023041303554018000_32.13.4562.9","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1825"},{"key":"2023041303554018000_32.13.4562.10","doi-asserted-by":"publisher","DOI":"10.1007\/s002130000588"},{"key":"2023041303554018000_32.13.4562.11","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/s00213-002-1335-4","article-title":"Antidepressant-like effects in various mice strains in the forced swimming test","volume":"166","author":"David","year":"2003","journal-title":"Psychopharmacology (Berl)"},{"key":"2023041303554018000_32.13.4562.12","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1097\/00001756-199703240-00023","article-title":"Scopolamine-induced deficits in a two-trial object recognition task in mice","volume":"8","author":"Dodart","year":"1997","journal-title":"Neuroreport"},{"key":"2023041303554018000_32.13.4562.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.08.029"},{"key":"2023041303554018000_32.13.4562.14","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1097\/00005053-199412000-00003","article-title":"Molecular psychiatry. 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