Common DISC1 polymorphisms disrupt Wnt/GSK3β signaling and brain development.
Common DISC1 polymorphisms disrupt Wnt/GSK3β signaling and brain development.
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DOI：
10.1016/j.neuron.2011.09.030
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发表时间：
2011-11-17
期刊：
影响因子：
16.2
通讯作者：
Tsai LH
中科院分区：
文献类型：
--
作者：
Singh KK;De Rienzo G;Drane L;Mao Y;Flood Z;Madison J;Ferreira M;Bergen S;King C;Sklar P;Sive H;Tsai LH
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 to 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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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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期刊：
The American journal of psychiatry
影响因子：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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