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

Fei Ye, Eunchai Kang, Chuan Yu, Xuyu Qian, Fadi Jacob, Cong Yu, Mao Mao, Randy Y.C. Poon, Jieun Kim, Hongjun Song, Guo li Ming*, Mingjie Zhang

*Corresponding author for this work

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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. 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.

Original languageEnglish
Pages (from-to)1041-1054.e5
Number of pages15
JournalNeuron
Volume96
Issue number5
Early online date2 Nov 2017
DOIs
Publication statusPublished - 6 Dec 2017

Keywords

  • cell cycle
  • complex structure
  • DISC1
  • human forebrain organoid
  • kinetochore attachment
  • NDE1
  • NDEL1
  • neurogenesis
  • psychiatric disorders

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    Ye, F., Kang, E., Yu, C., Qian, X., Jacob, F., Yu, C., Mao, M., Poon, R. Y. C., Kim, J., Song, H., Ming, G. L., & Zhang, M. (2017). DISC1 Regulates Neurogenesis via Modulating Kinetochore Attachment of Ndel1/Nde1 during Mitosis. Neuron, 96(5), 1041-1054.e5. https://doi.org/10.1016/j.neuron.2017.10.010