DISC1 Regulates Neurogenesis via Modulating Kinetochore Attachment of Ndel1/Nde1 during Mitosis

• Published in: Neuron (Cambridge, Mass.) Vol. 96; no. 5; pp. 1041 - 1054.e5
• Main Authors: Ye, Fei, Kang, Eunchai, Yu, Chuan, Qian, Xuyu, Jacob, Fadi, Yu, Cong, Mao, Mao, Poon, Randy Y.C., Kim, Jieun, Song, Hongjun, Ming, Guo-li, Zhang, Mingjie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.12.2017; Elsevier Limited
• Subjects: Attachment; Behavior disorders; Cell cycle; complex structure; DISC1; Disc1 protein; Forebrain; Glial cells; human forebrain organoid; Inhibitory postsynaptic potentials; kinetochore attachment; Localization; Mental disorders; Mitosis; Mutation; NDE1; NDEL1; Neurogenesis; Organoids; Pluripotency; Proteins; psychiatric disorders; Radial glial cells; Schizophrenia; Stem cell transplantation; Stem cells; Zika virus; complex structure; human forebrain organoid; cell cycle; NDE1; neurogenesis; DISC1; psychiatric disorders; NDEL1; kinetochore attachment
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2017.10.010

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. •High-resolution structure of DISC1/Ndel1 complex is solved by NMR spectroscopy•DISC1/Ndel1 interaction regulates Ndel1’s kinetochore localization•DISC1/Ndel1 interaction regulates mitosis of neural stem cells in mice and human organoids•Mitosis delay is observed in the patient forebrain organoid with a DISC1 mutation Ye et al. use structural insights to uncover a functional interaction between psychiatric risk genes, DISC1 and Ndel1/Nde1, in regulating cell-cycle progression of neural stem cells during cortical development.