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Cell Rep. 2015 Sep 1;12(9):1414-29. doi: 10.1016/j.celrep.2015.07.061. Epub 2015 Aug 20.

Genomic DISC1 Disruption in hiPSCs Alters Wnt Signaling and Neural Cell Fate.

Author information

1
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Harvard MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA.
2
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
3
Neuroscience Research Institute, Department of Molecular Cellular and Developmental Biology, Biomolecular Science and Engineering Program, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
4
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: tyoung@rics.bwh.harvard.edu.

Abstract

Genetic and clinical association studies have identified disrupted in schizophrenia 1 (DISC1) as a candidate risk gene for major mental illness. DISC1 is interrupted by a balanced chr(1;11) translocation in a Scottish family in which the translocation predisposes to psychiatric disorders. We investigate the consequences of DISC1 interruption in human neural cells using TALENs or CRISPR-Cas9 to target the DISC1 locus. We show that disruption of DISC1 near the site of the translocation results in decreased DISC1 protein levels because of nonsense-mediated decay of long splice variants. This results in an increased level of canonical Wnt signaling in neural progenitor cells and altered expression of fate markers such as Foxg1 and Tbr2. These gene expression changes are rescued by antagonizing Wnt signaling in a critical developmental window, supporting the hypothesis that DISC1-dependent suppression of basal Wnt signaling influences the distribution of cell types generated during cortical development.

PMID:
26299970
PMCID:
PMC4558300
DOI:
10.1016/j.celrep.2015.07.061
[Indexed for MEDLINE]
Free PMC Article

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