Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling
Mania causes symptoms of hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep, which suggests that the dysfunction of the striatum, a critical component of the brain motor and reward system, can be causally associated with mania. However, detailed molecular pathoph...
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doaj-4e053be4199c424abb6fbcb1944be5a42020-11-24T23:59:33ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-06-011010.3389/fnmol.2017.00201276263Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 SignalingYeunkum Lee0Yeunkum Lee1Sun Gyun Kim2Bokyoung Lee3Yinhua Zhang4Yinhua Zhang5Yoonhee Kim6Shinhyun Kim7Shinhyun Kim8Eunjoon Kim9Eunjoon Kim10Hyojin Kang11Kihoon Han12Kihoon Han13Department of Neuroscience, College of Medicine, Korea UniversitySeoul, South KoreaDepartment of Biomedical Sciences, College of Medicine, Korea UniversitySeoul, South KoreaCenter for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS)Daejeon, South KoreaDepartment of Neuroscience, College of Medicine, Korea UniversitySeoul, South KoreaDepartment of Neuroscience, College of Medicine, Korea UniversitySeoul, South KoreaDepartment of Biomedical Sciences, College of Medicine, Korea UniversitySeoul, South KoreaDepartment of Neuroscience, College of Medicine, Korea UniversitySeoul, South KoreaDepartment of Neuroscience, College of Medicine, Korea UniversitySeoul, South KoreaDepartment of Biomedical Sciences, College of Medicine, Korea UniversitySeoul, South KoreaCenter for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS)Daejeon, South KoreaDepartment of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)Daejeon, South KoreaHPC-enabled Convergence Technology Research Division, Korea Institute of Science and Technology InformationDaejeon, South KoreaDepartment of Neuroscience, College of Medicine, Korea UniversitySeoul, South KoreaDepartment of Biomedical Sciences, College of Medicine, Korea UniversitySeoul, South KoreaMania causes symptoms of hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep, which suggests that the dysfunction of the striatum, a critical component of the brain motor and reward system, can be causally associated with mania. However, detailed molecular pathophysiology underlying the striatal dysfunction in mania remains largely unknown. In this study, we aimed to identify the molecular pathways showing alterations in the striatum of SH3 and multiple ankyrin repeat domains 3 (Shank3)-overexpressing transgenic (TG) mice that display manic-like behaviors. The results of transcriptome analysis suggested that mammalian target of rapamycin complex 1 (mTORC1) signaling may be the primary molecular signature altered in the Shank3 TG striatum. Indeed, we found that striatal mTORC1 activity, as measured by mTOR S2448 phosphorylation, was significantly decreased in the Shank3 TG mice compared to wild-type (WT) mice. To elucidate the potential underlying mechanism, we re-analyzed previously reported protein interactomes, and detected a high connectivity between Shank3 and several upstream regulators of mTORC1, such as tuberous sclerosis 1 (TSC1), TSC2 and Ras homolog enriched in striatum (Rhes), via 94 common interactors that we denominated “Shank3-mTORC1 interactome”. We noticed that, among the 94 common interactors, 11 proteins were related to actin filaments, the level of which was increased in the dorsal striatum of Shank3 TG mice. Furthermore, we could co-immunoprecipitate Shank3, Rhes and Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) proteins from the striatal lysate of Shank3 TG mice. By comparing with the gene sets of psychiatric disorders, we also observed that the 94 proteins of Shank3-mTORC1 interactome were significantly associated with bipolar disorder (BD). Altogether, our results suggest a protein interaction-mediated connectivity between Shank3 and certain upstream regulators of mTORC1 that might contribute to the abnormal striatal mTORC1 activity and to the manic-like behaviors of Shank3 TG mice.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00201/fullShank3mTORC1striatummaniaRhes |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yeunkum Lee Yeunkum Lee Sun Gyun Kim Bokyoung Lee Yinhua Zhang Yinhua Zhang Yoonhee Kim Shinhyun Kim Shinhyun Kim Eunjoon Kim Eunjoon Kim Hyojin Kang Kihoon Han Kihoon Han |
spellingShingle |
Yeunkum Lee Yeunkum Lee Sun Gyun Kim Bokyoung Lee Yinhua Zhang Yinhua Zhang Yoonhee Kim Shinhyun Kim Shinhyun Kim Eunjoon Kim Eunjoon Kim Hyojin Kang Kihoon Han Kihoon Han Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling Frontiers in Molecular Neuroscience Shank3 mTORC1 striatum mania Rhes |
author_facet |
Yeunkum Lee Yeunkum Lee Sun Gyun Kim Bokyoung Lee Yinhua Zhang Yinhua Zhang Yoonhee Kim Shinhyun Kim Shinhyun Kim Eunjoon Kim Eunjoon Kim Hyojin Kang Kihoon Han Kihoon Han |
author_sort |
Yeunkum Lee |
title |
Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling |
title_short |
Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling |
title_full |
Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling |
title_fullStr |
Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling |
title_full_unstemmed |
Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling |
title_sort |
striatal transcriptome and interactome analysis of shank3-overexpressing mice reveals the connectivity between shank3 and mtorc1 signaling |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Molecular Neuroscience |
issn |
1662-5099 |
publishDate |
2017-06-01 |
description |
Mania causes symptoms of hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep, which suggests that the dysfunction of the striatum, a critical component of the brain motor and reward system, can be causally associated with mania. However, detailed molecular pathophysiology underlying the striatal dysfunction in mania remains largely unknown. In this study, we aimed to identify the molecular pathways showing alterations in the striatum of SH3 and multiple ankyrin repeat domains 3 (Shank3)-overexpressing transgenic (TG) mice that display manic-like behaviors. The results of transcriptome analysis suggested that mammalian target of rapamycin complex 1 (mTORC1) signaling may be the primary molecular signature altered in the Shank3 TG striatum. Indeed, we found that striatal mTORC1 activity, as measured by mTOR S2448 phosphorylation, was significantly decreased in the Shank3 TG mice compared to wild-type (WT) mice. To elucidate the potential underlying mechanism, we re-analyzed previously reported protein interactomes, and detected a high connectivity between Shank3 and several upstream regulators of mTORC1, such as tuberous sclerosis 1 (TSC1), TSC2 and Ras homolog enriched in striatum (Rhes), via 94 common interactors that we denominated “Shank3-mTORC1 interactome”. We noticed that, among the 94 common interactors, 11 proteins were related to actin filaments, the level of which was increased in the dorsal striatum of Shank3 TG mice. Furthermore, we could co-immunoprecipitate Shank3, Rhes and Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) proteins from the striatal lysate of Shank3 TG mice. By comparing with the gene sets of psychiatric disorders, we also observed that the 94 proteins of Shank3-mTORC1 interactome were significantly associated with bipolar disorder (BD). Altogether, our results suggest a protein interaction-mediated connectivity between Shank3 and certain upstream regulators of mTORC1 that might contribute to the abnormal striatal mTORC1 activity and to the manic-like behaviors of Shank3 TG mice. |
topic |
Shank3 mTORC1 striatum mania Rhes |
url |
http://journal.frontiersin.org/article/10.3389/fnmol.2017.00201/full |
work_keys_str_mv |
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