TY - JOUR
T1 - Common DISC1 polymorphisms disrupt Wnt/GSK3β signaling and brain development
AU - Singh, Karun K.
AU - De Rienzo, Gianluca
AU - Drane, Laurel
AU - Mao, Yingwei
AU - Flood, Zachary
AU - Madison, Jon
AU - Ferreira, Manuel
AU - Bergen, Sarah
AU - King, Cillian
AU - Sklar, Pamela
AU - Sive, Hazel
AU - Tsai, Li Huei
N1 - Funding Information:
We would like to thank Tsai lab members and Stanley Center members for helpful discussions. We would like to give a special thanks to Janice Kranz, Kimberly Chambert, Doug Ruderfer, Doug Barker, Jennifer Moran, and Edward M. Scolnick for their intellectual input and logistical support. L.-H.T. is an investigator of the Howard Hughes Medical Institute and the director of the neurobiology program at the Stanley Center for Psychiatric Research. K.K.S. is a recipient of the Human Frontiers Science Program Long-term fellowship and an NSERC postdoctoral fellowship. Y.M. is a recipient of the National Alliance for Research on Schizophrenia and Depression Young Investigator Award. This work was partially supported by a NIH RO1 grant (MH091115) to L.-H.T. and a grant from the Stanley Center for Psychiatric Research to L.-H.T.
PY - 2011/11/17
Y1 - 2011/11/17
N2 - Disrupted in Schizophrenia-1 (DISC1) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function; however, it is unknown how this occurs. Here, we demonstrate using mouse, zebrafish, and human model systems that DISC1 variants are loss of function in Wnt/GSK3β signaling and disrupt brain development. The DISC1 variants A83V, R264Q, and L607F, but not S704C, do not activate Wnt signaling compared with wild-type DISC1 resulting in decreased neural progenitor proliferation. In zebrafish, R264Q and L607F could not rescue DISC1 knockdown-mediated aberrant brain development. Furthermore, human lymphoblast cell lines endogenously expressing R264Q displayed impaired Wnt signaling. Interestingly, S704C inhibited the migration of neurons in the developing neocortex. Our data demonstrate DISC1 variants impair Wnt signaling and brain development and elucidate a possible mechanism for their role in neuropsychiatric phenotypes.
AB - Disrupted in Schizophrenia-1 (DISC1) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function; however, it is unknown how this occurs. Here, we demonstrate using mouse, zebrafish, and human model systems that DISC1 variants are loss of function in Wnt/GSK3β signaling and disrupt brain development. The DISC1 variants A83V, R264Q, and L607F, but not S704C, do not activate Wnt signaling compared with wild-type DISC1 resulting in decreased neural progenitor proliferation. In zebrafish, R264Q and L607F could not rescue DISC1 knockdown-mediated aberrant brain development. Furthermore, human lymphoblast cell lines endogenously expressing R264Q displayed impaired Wnt signaling. Interestingly, S704C inhibited the migration of neurons in the developing neocortex. Our data demonstrate DISC1 variants impair Wnt signaling and brain development and elucidate a possible mechanism for their role in neuropsychiatric phenotypes.
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U2 - 10.1016/j.neuron.2011.09.030
DO - 10.1016/j.neuron.2011.09.030
M3 - Article
C2 - 22099458
AN - SCOPUS:81355150792
SN - 0896-6273
VL - 72
SP - 545
EP - 558
JO - Neuron
JF - Neuron
IS - 4
ER -