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Analysis of induced pluripotent stem cells carrying 22q11.2 deletion

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posted on 2024-08-06, 10:54 authored by M. Toyoshima, W. Akamatsu, Y. Okada, T. Ohnishi, S. Balan, Y. Hisano, Y. Iwayama, T. Toyota, T. Matsumoto, N. Itasaka, S. Sugiyama, M. Tanaka, M. Yano, Brian Dean, H. Okano, T. Yoshikawa
Given the complexity and heterogeneity of the genomic architecture underlying schizophrenia, molecular analyses of these patients with defined and large effect-size genomic defects could provide valuable clues. We established human-induced pluripotent stem cells from two schizophrenia patients with the 22q11.2 deletion (two cell lines from each subject, total of four cell lines) and three controls (total of four cell lines). Neurosphere size, neural differentiation efficiency, neurite outgrowth, cellular migration and the neurogenic-to-gliogenic competence ratio were significantly reduced in patient-derived cells. As an underlying mechanism, we focused on the role of DGCR8, a key gene for microRNA (miRNA) processing and mapped in the deleted region. In mice, Dgcr8 hetero-knockout is known to show a similar phenotype of reduced neurosphere size (Ouchi et al., 2013). The miRNA profiling detected reduced expression levels of miRNAs belonging to miR-17/92 cluster and miR-106a/b in the patient-derived neurospheres. Those miRNAs are reported to target p38α, and conformingly the levels of p38α were upregulated in the patient-derived cells. p38α is known to drive gliogenic differentiation. The inhibition of p38 activity by SB203580 in patient-derived neurospheres partially restored neurogenic competence. Furthermore, we detected elevated expression of GFAP, a gliogenic (astrocyte) marker, in postmortem brains from schizophrenia patients without the 22q11.2 deletion, whereas inflammation markers (IL1B and IL6) remained unchanged. In contrast, a neuronal marker, MAP2 expressions were decreased in schizophrenia brains. These results suggest that a dysregulated balance of neurogenic-to-gliogenic competence may underlie neurodevelopmental disorders such as schizophrenia.

Funding

Understanding the pathophysiology of schizophrenia, major depressive disorder and bipolar disorder as a basis for improving treatments

National Health and Medical Research Council

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ISSN

2158-3188

Journal title

Translational Psychiatry

Volume

6

Issue

11

Article number

article no. e934

Pagination

1 p

Publisher

Nature Publishing Group

Copyright statement

Copyright © 2016 The Authors. This article is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.

Language

eng

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