Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia.
Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia.
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DOI：
10.1186/1756-6606-7-21
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发表时间：
2014-03-29
期刊：
影响因子：
3.6
通讯作者：
Senda T
中科院分区：
文献类型：
--
作者：
Onouchi T;Kobayashi K;Sakai K;Shimomura A;Smits R;Sumi-Ichinose C;Kurosumi M;Takao K;Nomura R;Iizuka-Kogo A;Suzuki H;Kondo K;Akiyama T;Miyakawa T;Fodde R;Senda T
腺瘤性结肠息肉病（APC）基因功能的丧失导致经典Wnt通路的组成性激活，并代表结直肠肿瘤发生中的主要起始和限速事件。APC可能通过其不同的功能域参与广泛的生物学功能，并且在脑和外周组织中大量表达。然而，APC的神经元功能知之甚少。为了研究Apc在中枢神经系统中的功能作用，我们分析了Apc 1638 T/1638 T小鼠的神经学表型，这些小鼠携带Apc 3′末端三分之一的靶向缺失，但不影响Wnt信号传导。一系列行为测试显示Apc 1638 T/1638 T小鼠存在工作记忆缺陷、自发活动增加、焦虑相关行为减少和社会互动轻度减少。Apc 1638 T/1638 T小鼠海马CA 1区的树突棘形态异常，突触传递的长时程增强功能受损。此外，Apc 1638 T/1638 T小鼠在脑中显示出异常的多巴胺和5-羟色胺分布。这些行为和神经元表型中的一些与精神分裂症的症状和内表型相关。我们的研究结果表明，C-末端的APC肿瘤抑制剂在认知和神经精神功能中起着至关重要的作用。这一发现表明APC的C末端与中枢神经系统的病理之间存在潜在的功能联系。
Loss of adenomatous polyposis coli (APC) gene function results in constitutive activation of the canonical Wnt pathway and represents the main initiating and rate-limiting event in colorectal tumorigenesis. APC is likely to participate in a wide spectrum of biological functions via its different functional domains and is abundantly expressed in the brain as well as in peripheral tissues. However, the neuronal function of APC is poorly understood. To investigate the functional role of Apc in the central nervous system, we analyzed the neurological phenotypes of Apc1638T/1638T mice, which carry a targeted deletion of the 3′ terminal third of Apc that does not affect Wnt signaling. A series of behavioral tests revealed a working memory deficit, increased locomotor activity, reduced anxiety-related behavior, and mildly decreased social interaction in Apc1638T/1638T mice. Apc1638T/1638T mice showed abnormal morphology of the dendritic spines and impaired long-term potentiation of synaptic transmission in the hippocampal CA1 region. Moreover, Apc1638T/1638T mice showed abnormal dopamine and serotonin distribution in the brain. Some of these behavioral and neuronal phenotypes are related to symptoms and endophenotypes of schizophrenia. Our results demonstrate that the C-terminus of the Apc tumor suppressor plays a critical role in cognitive and neuropsychiatric functioning. This finding suggests a potential functional link between the C-terminus of APC and pathologies of the central nervous system.
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DOI：
10.1523/jneurosci.1815-08.2008
发表时间：
2008-07-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chen YJ;Johnson MA;Lieberman MD;Goodchild RE;Schobel S;Lewandowski N;Rosoklija G;Liu RC;Gingrich JA;Small S;Moore H;Dwork AJ;Talmage DA;Role LW
通讯作者：
Role LW
影响因子：
3.4
作者：
Henseler, I.;Falkai, P.;Gruber, O.
通讯作者：
Gruber, O.
影响因子：
3.4
作者：
Shimomura, Atsushi;Ohkuma, Mahito;Senda, Takao
通讯作者：
Senda, Takao
影响因子：
3.7
作者：
Chen G;Wang LP;Tsien JZ
通讯作者：
Tsien JZ
影响因子：
1.7
作者：
Chen, YC;Bourne, J;Fitzsimonds, RM
通讯作者：
Fitzsimonds, RM