Striatal transcriptome and interactome analysis of Shank3-overexpressing mice reveals the connectivity between Shank3 and mTORC1 signaling

Yeunkum Lee, Sun Gyun Kim, Bokyoung Lee, Yinhua Zhang, Yoonhee Kim, Shinhyun Kim, Eunjoon Kim, Hyojin Kang, Kihoon Han

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number201
JournalFrontiers in Molecular Neuroscience
Volume10
DOIs
Publication statusPublished - 2017 Jun 28

Fingerprint

Corpus Striatum
Gene Expression Profiling
Transgenic Mice
Bipolar Disorder
Wiskott-Aldrich Syndrome Protein Family
Proteins
Ankyrin Repeat
Impulsive Behavior
mechanistic target of rapamycin complex 1
Actin Cytoskeleton
Reward
Psychiatry
Sleep
Anxiety
Phosphorylation
Brain

Keywords

  • Mania
  • MTORC1
  • Rhes
  • Shank3
  • Striatum

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Striatal transcriptome and interactome analysis of Shank3-overexpressing mice reveals the connectivity between Shank3 and mTORC1 signaling. / Lee, Yeunkum; Kim, Sun Gyun; Lee, Bokyoung; Zhang, Yinhua; Kim, Yoonhee; Kim, Shinhyun; Kim, Eunjoon; Kang, Hyojin; Han, Kihoon.

In: Frontiers in Molecular Neuroscience, Vol. 10, 201, 28.06.2017.

Research output: Contribution to journalArticle

Lee, Yeunkum ; Kim, Sun Gyun ; Lee, Bokyoung ; Zhang, Yinhua ; Kim, Yoonhee ; Kim, Shinhyun ; Kim, Eunjoon ; Kang, Hyojin ; Han, Kihoon. / Striatal transcriptome and interactome analysis of Shank3-overexpressing mice reveals the connectivity between Shank3 and mTORC1 signaling. In: Frontiers in Molecular Neuroscience. 2017 ; Vol. 10.
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