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

Abstract

SUMMARY 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 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 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 has implications for how genetic insults may contribute to psychiatric disorders.

The ethics of experimenting with human brain tissue

“…Already, researchers have deployed brain organoids to investigate neurodevelopmental alterations in people with autism spectrum disorders 8,10 or schizophrenia 11 , and to study the unusually small brain size (microcephaly) seen in some babies infected with the Zika virus before birth 12 .…”

Disorder mediated oligomerization of DISC1 proteins revealed by coarse-grained computer simulations

“…Zhang and coworkers have recently solved the atomic structure of DISC1 C-terminal tail (aa. 765-835) in complex with Nde1, revealing a helix-turn-helix structure (16), which was later confirmed by SAXS (17). Overall, the C-terminal region appears to possess the characteristics of a series of helical bundles that mediate protein-protein interactions.…”

Applications of Human Brain Organoids to Clinical Problems

“…DLX6‐AS1 and DLX1 , which are involved in interneuron differentiation, are among the top differentially expressed genes in CHD8 knockout heterozygote compared with control organoids (Wang et al, ). Similar studies using patient‐derived organoids and organoids overexpressing a disease gene have been performed in schizophrenia (Ye et al, ). These studies are the vanguard of organoid‐based investigations of neuropsychiatric and neurocognitive disorders.…”