Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia

Takanori Onouchi, Katsunori Kobayashi, Kazuyoshi Sakai, Atsushi Shimomura, Ron Smits, Chiho Ichinose, Masafumi Kurosumi, Keizo Takao, Ryuji Nomura, Akiko Iizuka-Kogo, Hidenori Suzuki, Kazunao Kondo, Tetsu Akiyama, Tsuyoshi Miyakawa, Riccardo Fodde, Takao Senda

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: 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 Apc 1638T/1638T mice, which carry a targeted deletion of the 3′ terminal third of Apc that does not affect Wnt signaling. Results: A series of behavioral tests revealed a working memory deficit, increased locomotor activity, reduced anxiety-related behavior, and mildly decreased social interaction in Apc 1638T/1638T mice. Apc 1638T/1638T mice showed abnormal morphology of the dendritic spines and impaired long-term potentiation of synaptic transmission in the hippocampal CA1 region. Moreover, Apc 1638T/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. Conclusions: 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.

Original languageEnglish
Article number21
JournalMolecular Brain
Volume7
Issue number1
DOIs
Publication statusPublished - 29-03-2014

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Adenomatous Polyposis Coli
Nervous System
Schizophrenia
Phenotype
Neoplasms
Central Nervous System
APC Genes
Endophenotypes
Hippocampal CA1 Region
Dendritic Spines
Wnt Signaling Pathway
Long-Term Potentiation
Memory Disorders
Brain
Locomotion
Interpersonal Relations
Short-Term Memory
Synaptic Transmission
Dopamine
Serotonin

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Onouchi, Takanori ; Kobayashi, Katsunori ; Sakai, Kazuyoshi ; Shimomura, Atsushi ; Smits, Ron ; Ichinose, Chiho ; Kurosumi, Masafumi ; Takao, Keizo ; Nomura, Ryuji ; Iizuka-Kogo, Akiko ; Suzuki, Hidenori ; Kondo, Kazunao ; Akiyama, Tetsu ; Miyakawa, Tsuyoshi ; Fodde, Riccardo ; Senda, Takao. / Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia. In: Molecular Brain. 2014 ; Vol. 7, No. 1.
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abstract = "Background: 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 Apc 1638T/1638T mice, which carry a targeted deletion of the 3′ terminal third of Apc that does not affect Wnt signaling. Results: A series of behavioral tests revealed a working memory deficit, increased locomotor activity, reduced anxiety-related behavior, and mildly decreased social interaction in Apc 1638T/1638T mice. Apc 1638T/1638T mice showed abnormal morphology of the dendritic spines and impaired long-term potentiation of synaptic transmission in the hippocampal CA1 region. Moreover, Apc 1638T/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. Conclusions: 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.",
author = "Takanori Onouchi and Katsunori Kobayashi and Kazuyoshi Sakai and Atsushi Shimomura and Ron Smits and Chiho Ichinose and Masafumi Kurosumi and Keizo Takao and Ryuji Nomura and Akiko Iizuka-Kogo and Hidenori Suzuki and Kazunao Kondo and Tetsu Akiyama and Tsuyoshi Miyakawa and Riccardo Fodde and Takao Senda",
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Onouchi, T, Kobayashi, K, Sakai, K, Shimomura, A, Smits, R, Ichinose, C, Kurosumi, M, Takao, K, Nomura, R, Iizuka-Kogo, A, Suzuki, H, Kondo, K, Akiyama, T, Miyakawa, T, Fodde, R & Senda, T 2014, 'Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia', Molecular Brain, vol. 7, no. 1, 21. https://doi.org/10.1186/1756-6606-7-21

Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia. / Onouchi, Takanori; Kobayashi, Katsunori; Sakai, Kazuyoshi; Shimomura, Atsushi; Smits, Ron; Ichinose, Chiho; Kurosumi, Masafumi; Takao, Keizo; Nomura, Ryuji; Iizuka-Kogo, Akiko; Suzuki, Hidenori; Kondo, Kazunao; Akiyama, Tetsu; Miyakawa, Tsuyoshi; Fodde, Riccardo; Senda, Takao.

In: Molecular Brain, Vol. 7, No. 1, 21, 29.03.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia

AU - Onouchi, Takanori

AU - Kobayashi, Katsunori

AU - Sakai, Kazuyoshi

AU - Shimomura, Atsushi

AU - Smits, Ron

AU - Ichinose, Chiho

AU - Kurosumi, Masafumi

AU - Takao, Keizo

AU - Nomura, Ryuji

AU - Iizuka-Kogo, Akiko

AU - Suzuki, Hidenori

AU - Kondo, Kazunao

AU - Akiyama, Tetsu

AU - Miyakawa, Tsuyoshi

AU - Fodde, Riccardo

AU - Senda, Takao

PY - 2014/3/29

Y1 - 2014/3/29

N2 - Background: 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 Apc 1638T/1638T mice, which carry a targeted deletion of the 3′ terminal third of Apc that does not affect Wnt signaling. Results: A series of behavioral tests revealed a working memory deficit, increased locomotor activity, reduced anxiety-related behavior, and mildly decreased social interaction in Apc 1638T/1638T mice. Apc 1638T/1638T mice showed abnormal morphology of the dendritic spines and impaired long-term potentiation of synaptic transmission in the hippocampal CA1 region. Moreover, Apc 1638T/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. Conclusions: 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.

AB - Background: 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 Apc 1638T/1638T mice, which carry a targeted deletion of the 3′ terminal third of Apc that does not affect Wnt signaling. Results: A series of behavioral tests revealed a working memory deficit, increased locomotor activity, reduced anxiety-related behavior, and mildly decreased social interaction in Apc 1638T/1638T mice. Apc 1638T/1638T mice showed abnormal morphology of the dendritic spines and impaired long-term potentiation of synaptic transmission in the hippocampal CA1 region. Moreover, Apc 1638T/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. Conclusions: 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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