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

• Published in: Translational psychiatry Vol. 6; no. 11; p. e934
• Main Authors: Toyoshima, M, Akamatsu, W, Okada, Y, Ohnishi, T, Balan, S, Hisano, Y, Iwayama, Y, Toyota, T, Matsumoto, T, Itasaka, N, Sugiyama, S, Tanaka, M, Yano, M, Dean, B, Okano, H, Yoshikawa, T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2016; Nature Publishing Group
• Subjects: 22q11 Deletion Syndrome - genetics; 22q11 Deletion Syndrome - pathology; 45/61; 45/77; 631/378/340; 692/699/476/1799; 82/80; Adolescent; Adult; Behavioral Sciences; Biological Psychology; Brain - metabolism; Brain - pathology; Case-Control Studies; Cell Line; DNA Copy Number Variations; Female; Genetic Carrier Screening; Genetic Heterogeneity; Genetic Predisposition to Disease - genetics; Humans; Male; Medicine; Medicine & Public Health; MicroRNAs - genetics; Neurons; Neurosciences; Original; original-article; Pharmacotherapy; Phenotype; Pluripotent Stem Cells - metabolism; Pluripotent Stem Cells - pathology; Psychiatry; RNA-Binding Proteins - genetics; Schizophrenia - genetics; Schizophrenia - pathology
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/tp.2016.206

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.