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 language | English |
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Pages (from-to) | 1041-1054.e5 |
Number of pages | 15 |
Journal | Neuron |
Volume | 96 |
Issue number | 5 |
Early online date | 2 Nov 2017 |
DOIs | |
Publication status | Published - 6 Dec 2017 |
Externally published | Yes |
Bibliographical note
Data Resources: The atomic coordinates of the DISC1/Ndel1 complex are deposited to the Protein Data Bank under the accession codes PDB: 5YI4.Author Contributions: F.Y., Chuan Yu, Cong Yu, M.M., and R.Y.C.P. contributed to structural analysis. E.K. performed functional analysis of mouse and organoid development. X.Q. and F.J. helped with organoid analyses. J.K. contributed to data collection. F.Y., E.K., H.S., G.M., and M.Z. conceived the project and wrote the manuscript.
Acknowledgments: We thank S. Hirotsune for anti-Ndel1 antibody and members of the Ming, Song, and Zhang laboratories for comments. This work was supported by grants from RGC of Hong Kong (664113, 16103614, AoE-M09-12, and T13-607/12R) and a 973 program grant from the Minister of Science and Technology of China (2014CB910204 to M.Z.), the NIH (R35NS097370, R01MH105128, and U19AI131130 to G.M.; R37NS047344 and U19 MH106434 to H.S.), the Simons Foundation (SFARI grant 308988 to H.S. and SFARI grant 401625 to G.M.), and the NARSAD young investigator award (119228 to E.K.). M.Z. is a Kerry Holdings Professor in Science and a Senior Fellow of IAS at HKUST.
Keywords
- cell cycle
- complex structure
- DISC1
- human forebrain organoid
- kinetochore attachment
- NDE1
- NDEL1
- neurogenesis
- psychiatric disorders