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

doi:10.1016/j.neuron.2017.10.010

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.

Authors

Fei Ye¹, Eunchai Kang², Chuan Yu³, Xuyu Qian⁴, Fadi Jacob⁵, Cong Yu³, Mao Mao³, Randy Y C Poon³, Jieun Kim⁶, Hongjun Song⁷, Guo-Li Ming⁸, Mingjie Zhang⁹

Affiliations

¹ Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Center of Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
² Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
⁴ Biomedical Engineering Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Biomedical Engineering Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: gming@pennmedicine.upenn.edu.
⁹ Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Center of Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Electronic address: mzhang@ust.hk.

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.

Keywords: DISC1; NDE1; NDEL1; cell cycle; complex structure; human forebrain organoid; kinetochore attachment; neurogenesis; psychiatric disorders.

MeSH terms

Animals
Carrier Proteins / chemistry
Carrier Proteins / genetics*
Carrier Proteins / physiology*
Cell Cycle
Female
HeLa Cells
Humans
Immunohistochemistry
Male
Mice
Mitosis / genetics*
Models, Molecular
Nerve Tissue Proteins / chemistry
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / physiology*
Neural Stem Cells
Neurogenesis / genetics*
Neurons / pathology
Neurons / physiology*
Pluripotent Stem Cells
Pregnancy
Protein Binding
Schizophrenia / pathology

Substances

Carrier Proteins
DISC1 protein, human
NDEL1 protein, human
Nerve Tissue Proteins

Abstract

MeSH terms

Substances

Grants and funding