| Structural highlights
Function
[DISC1_MOUSE] Involved in the regulation of multiple aspects of embryonic and adult neurogenesis. Required for neural progenitor proliferation in the ventrical/subventrical zone during embryonic brain development and in the adult dentate gyrus of the hippocampus. Participates in the Wnt-mediated neural progenitor proliferation as a positive regulator by modulating GSK3B activity and CTNNB1 abundance. Plays a role as a modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including neuron positioning, dendritic development and synapse formation. Inhibits the activation of AKT-mTOR signaling upon interaction with CCDC88A. Regulates the migration of early-born granule cell precursors toward the dentate gyrus during the hippocampal development. Plays a role, together with PCNT, in the microtubule network formation.[1] [2] [3] [4]
Publication Abstract from PubMed
Mutations of DISC1 (disrupted-in-schizophrenia 1) have been associated with major psychiatric disorders. Despite the hundreds of DISC1-binding proteins reported, almost nothing is known about how DISC1 interacts with other proteins structurally to impact human brain development. Here we solved the high-resolution structure of DISC1 C-terminal tail in complex with its binding domain of Ndel1. Mechanistically, DISC1 regulates Ndel1's kinetochore attachment, but not its centrosome localization, during mitosis. Functionally, disrupting DISC1/Ndel1 complex formation prolongs mitotic length and interferes with cell-cycle progression in human cells, and it causes cell-cycle deficits of radial glial cells in the embryonic mouse cortex and human forebrain organoids. We also observed similar deficits in organoids derived from schizophrenia patient induced pluripotent stem cells (iPSCs) with a DISC1 mutation that disrupts its interaction with Ndel1. Our study uncovers a new mechanism of action for DISC1 based on its structure, and it has implications for how genetic insults may contribute to psychiatric disorders.
DISC1 Regulates Neurogenesis via Modulating Kinetochore Attachment of Ndel1/Nde1 during Mitosis.,Ye F, Kang E, Yu C, Qian X, Jacob F, Yu C, Mao M, Poon RYC, Kim J, Song H, Ming GL, Zhang M Neuron. 2017 Dec 6;96(5):1041-1054.e5. doi: 10.1016/j.neuron.2017.10.010. Epub, 2017 Nov 2. PMID:29103808[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007 Sep 21;130(6):1146-58. Epub 2007 Sep 6. PMID:17825401 doi:http://dx.doi.org/10.1016/j.cell.2007.07.010
- ↑ Mao Y, Ge X, Frank CL, Madison JM, Koehler AN, Doud MK, Tassa C, Berry EM, Soda T, Singh KK, Biechele T, Petryshen TL, Moon RT, Haggarty SJ, Tsai LH. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 2009 Mar 20;136(6):1017-31. doi: 10.1016/j.cell.2008.12.044. PMID:19303846 doi:http://dx.doi.org/10.1016/j.cell.2008.12.044
- ↑ Meyer KD, Morris JA. Disc1 regulates granule cell migration in the developing hippocampus. Hum Mol Genet. 2009 Sep 1;18(17):3286-97. doi: 10.1093/hmg/ddp266. Epub 2009 Jun , 5. PMID:19502360 doi:http://dx.doi.org/10.1093/hmg/ddp266
- ↑ Kim JY, Duan X, Liu CY, Jang MH, Guo JU, Pow-anpongkul N, Kang E, Song H, Ming GL. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron. 2009 Sep 24;63(6):761-73. doi: 10.1016/j.neuron.2009.08.008. PMID:19778506 doi:http://dx.doi.org/10.1016/j.neuron.2009.08.008
- ↑ Ye F, Kang E, Yu C, Qian X, Jacob F, Yu C, Mao M, Poon RYC, Kim J, Song H, Ming GL, Zhang M. DISC1 Regulates Neurogenesis via Modulating Kinetochore Attachment of Ndel1/Nde1 during Mitosis. Neuron. 2017 Dec 6;96(5):1041-1054.e5. doi: 10.1016/j.neuron.2017.10.010. Epub, 2017 Nov 2. PMID:29103808 doi:http://dx.doi.org/10.1016/j.neuron.2017.10.010
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