Convergence of independent DISC1 mutations on impaired neurite growth via decreased UNC5D expression

• Type of Material: Article
• Authors: Priya Srikanth, Brigham & Womens Hospital; Valentina N. Lagomarsino, Brigham & Womens Hospital; Richard V. Pearse, Brigham & Womens Hospital; Meichen Liao, Brigham & Womens Hospital; Sulagna Ghosh, Harvard University; Ralda Nehme, Harvard University; Nicholas Seyfried, Emory University; Kevin Eggan, Harvard University; Tracy L. Young-Pearse, Brigham & Womens Hospital
• Language: English
• Date: 2018-11-08
• Publisher: Springer Nature [academic journals on nature.com]: Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41398-018-0281-9
• Title of Journal or Parent Work: Translational Psychiatry
• ISSN: 2158-3188
• Volume: 8
• Issue: 1
• Start Page: 245
• End Page: 245
• Grant/Funding Information: This work was supported by 01MH101148 and R01MH101148-S1, and the Brain and Behavior Research Foundation (TYP).
• Keywords: ALZHEIMERS-DISEASE; PLURIPOTENT STEM-CELLS; DE-NOVO MUTATIONS; IN-SCHIZOPHRENIA 1; MAJOR MENTAL-ILLNESS; Science & Technology; Life Sciences & Biomedicine; GENETIC RISK-FACTOR; FUNCTIONAL-NEURONS; IPSC-DERIVED NEURONS; CEREBRAL-CORTEX DEVELOPMENT; Psychiatry; INDUCED NEURONAL CELLS
• Research Categories: Psychology, Clinical

Abstract

The identification of convergent phenotypes in different models of psychiatric illness highlights robust phenotypes that are more likely to be implicated in disease pathophysiology. Here, we utilize human iPSCs harboring distinct mutations in DISC1 that have been found in families with major mental illness. One mutation was engineered to mimic the consequences on DISC1 protein of a balanced translocation linked to mental illness in a Scottish pedigree; the other mutation was identified in an American pedigree with a high incidence of mental illness. Directed differentiation of these iPSCs using NGN2 expression shows rapid conversion to a homogenous population of mature excitatory neurons. Both DISC1 mutations result in reduced DISC1 protein expression, and show subtle effects on certain presynaptic proteins. In addition, RNA sequencing and qPCR showed decreased expression of UNC5D, DPP10, PCDHA6, and ZNF506 in neurons with both DISC1 mutations. Longitudinal analysis of neurite outgrowth revealed decreased neurite outgrowth in neurons with each DISC1 mutation, which was mimicked by UNC5D knockdown and rescued by transient upregulation of endogenous UNC5D. This study shows a narrow range of convergent phenotypes of two mutations found in families with major mental illness, and implicates dysregulated netrin signaling in DISC1 biology.