Year: 2015
Type: article
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.
Source: Cell Reports
Authors: Priya Srikanth, Karam Han, Dana G. Callahan, Eugenia Makovkina, Christina R. Muratore, Matthew A. Lalli, Honglin Zhou, Justin D. Boyd, Kenneth S. Kosik, Dennis J. Selkoe, Tracy L. Young-Pearse
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: Identifying critical functions of DISC1 disrupted in major mental illness, Medical Scientist Training Program, Genes and developmental signaling pathways in neuropsychiatric disorders, Functions of DISC1 and APP in Cortical Development and Neuropsychiatric Disorders, Aging in the Brain: Role of the Fibrous Proteins, Training in the Molecular Biology of Neurodegeneration and Alzheimer's Disease
OpenAlex ID: W1635914561