在诱导多能干细胞（iPSCs）和小鼠中模拟精神分裂症的遗传风险揭示了与黏着连接和极性相关的神经干细胞缺陷。
Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity.
作者信息
Yoon Ki-Jun, Nguyen Ha Nam, Ursini Gianluca, Zhang Fengyu, Kim Nam-Shik, Wen Zhexing, Makri Georgia, Nauen David, Shin Joo Heon, Park Youngbin, Chung Raeeun, Pekle Eva, Zhang Ce, Towe Maxwell, Hussaini Syed Mohammed Qasim, Lee Yohan, Rujescu Dan, St Clair David, Kleinman Joel E, Hyde Thomas M, Krauss Gregory, Christian Kimberly M, Rapoport Judith L, Weinberger Daniel R, Song Hongjun, Ming Guo-Li
机构信息
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
出版信息
Cell Stem Cell. 2014 Jul 3;15(1):79-91. doi: 10.1016/j.stem.2014.05.003.
Defects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signaling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.
大脑发育缺陷被认为与神经精神疾病的发病有关，但确定具体的潜在机制已被证明很困难。在这里，我们采用了多方面的方法来研究为什么15q11.2拷贝数变异是精神分裂症和自闭症的突出风险因素。首先，我们表明携带15q11.2微缺失的人诱导多能干细胞衍生的神经祖细胞在黏着连接和顶端极性方面存在缺陷。这是由于CYFIP1单倍体不足所致，CYFIP1是15q11.2内的一个基因，编码WAVE复合体的一个亚基，该复合体调节细胞骨架动力学。在发育中的小鼠皮层中，CYFIP1和WAVE信号的缺陷同样会影响放射状胶质细胞，导致它们在脑室区外异位定位。最后，有针对性的人类基因关联分析揭示了CYFIP1与WAVE信号介质ACTR2之间的上位性相互作用以及精神分裂症风险。我们的研究结果为CYFIP1如何调节神经干细胞功能提供了见解，并可能有助于解释神经精神疾病的易感性。
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