DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212
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Disrupted-in-schizophrenia 1 (DISC1), a susceptibility gene for major mental illnesses, regulates multiple aspects of embryonic and adult neurogenesis. Here, we show that DISC1 suppression in newborn neurons of the adult hippocampus leads to overactivated signaling of AKT, another schizophrenia susceptibility gene. Mechanistically, DISC1 directly interacts with KIAA1212, an AKT binding partner that enhances AKT signaling in the absence of DISC1, and DISC1 binding to KIAA1212 prevents AKT activation in vitro. Functionally, multiple genetic manipulations to enhance AKT signaling in adult-born neurons in vivo exhibit similar defects as DISC1 suppression in neuronal development that can be rescued by pharmacological inhibition of mammalian target of rapamycin (mTOR), an AKT downstream effector. Our study identifies the AKT-mTOR signaling pathway as a critical DISC1 target in regulating neuronal development and provides a framework for understanding how multiple susceptibility genes may functionally converge onto a common pathway in contributing to the etiology of certain psychiatric disorders.
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Synaptic dysfunction and abnormal behaviors have been documented in mice harboring Disc1 mutations.
“Synaptic dysfunction and abnormal behaviors have been documented in mice harboring Disc1 mutations (Clapcote et al., 2007; Kim et al., 2009)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Kim et al., 2009
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- Authors
- Kim, J. Y., Duan, X., Liu, C. Y., Jang, M.-H., Guo, J. U., Pow-anpongkul, N., Kang, E., Song, H., & Ming, G.-L.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Ming, Guo-li
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 63
- Issue
- 6
- Pages
- 761-773
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3075620
- OpenAlex
- W2067961999
- Cited by
- 319
- References
- 71
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 11 · 2023: 8 · 2022: 15 · 2021: 12 · 2020: 11 · 2019: 14 · 2018: 20 · 2017: 12 · 2016: 23 · 2015: 32 · 2014: 24 · 2013: 26 · 2012: 32
- FWCI
- 10.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG 024984, R01AG024984)
- National Institute of Mental Health (MH084018, P20MH084018)
- National Institute of Neurological Disorders and Stroke (NS 048271, R01NS047344, NS 047344, R01NS048271, R37NS047344, R56NS047344)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD069184)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- DISC1, Akt signaling, mTOR signaling, adult neurogenesis, adult hippocampus, newborn neurons, schizophrenia risk genes, protein-protein interaction
- MeSH terms
- Analysis of Variance, Animals, Animals, Newborn, Cell Movement, Cells, Cultured, Female, Hippocampus, Humans, Immunosuppressive Agents, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, Pregnancy, Protein Binding, Transfection, Signal Transduction, Gene Expression Regulation, Developmental, Sirolimus, RNA Interference, Immunoprecipitation, Green Fluorescent Proteins, Oncogene Protein v-akt, Mice, Adult Stem Cells, Neurogenesis, Gene Knockdown Techniques
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