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

Molecular Brain - Tập 7 - Trang 1-14 - 2014
Takanori Onouchi1,2, Katsunori Kobayashi3,4, Kazuyoshi Sakai5, Atsushi Shimomura1, Ron Smits6, Chiho Sumi-Ichinose7, Masafumi Kurosumi8, Keizo Takao4,9,10,11, Ryuji Nomura1, Akiko Iizuka-Kogo1,12, Hidenori Suzuki3,4, Kazunao Kondo7, Tetsu Akiyama13, Tsuyoshi Miyakawa4,9,10,11, Riccardo Fodde14, Takao Senda1,15
1Department of Anatomy I, Fujita Health University School of Medicine, Toyoake, Japan
2Department of Pathology I, Fujita Health University School of Medicine, Toyoake, Japan
3Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
4Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Saitama, Japan
5Department of Anatomy, Faculty of Clinical Engineering, Fujita Health University School of Health Sciences, Toyoake, Japan
6Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
7Department of Pharmacology, Fujita Health University School of Medicine, Toyoake, Japan
8Department of Pathology, Saitama Cancer Center, Ina, Japan
9Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences,Myodaiji, Okazaki, Japan
10Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan
11Genetic Engineering and Functional Genomics Group, Frontier Technology Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
12Department of Anatomy and Cell Biology, Gunma University Graduate School of Medicine, Maebashi, Japan
13Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan
14Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam, The Netherlands
15Department of Anatomy, Gifu University Graduate School of Medicine, Gifu, Japan

Tóm tắt

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, 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. 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.

Tài liệu tham khảo

Fodde R, Smits R, Clevers H: APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer. 2001, 1: 55-67. 10.1038/35094067. Bhat RV, Baraban JM, Johnson RC, Eipper BA, Mains RE: High levels of expression of the tumor suppressor gene APC during development of the rat central nervous system. J Neurosci. 1994, 14: 3059-3071. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, Burger PC, Wood PA, Taqi F, Booker SV, Petersen GM, Offerhaus GJA, Tersmette AC, Giardiello FM, Vogelstein B, Kinzler KW: The molecular basis of Turcot’s syndrome. N Engl J Med. 1995, 332: 839-847. 10.1056/NEJM199503303321302. Senda T, Iizuka-Kogo A, Onouchi T, Shimomura A: Adenomatous polyposis coli (APC) plays multiple roles in the intestinal and colorectal epithelia. Med Mol Morphol. 2007, 40: 68-81. 10.1007/s00795-006-0352-5. Fodde R: The multiple functions of tumour suppressors: it’s all in APC. Nat Cell Biol. 2003, 5: 190-192. 10.1038/ncb0303-190. Yang Z, Ma X, Wang Y, Wang J, Xiang B, Wu J, Deng W, Li M, Wang Q, Li T: Association of APC and REEP5 gene polymorphisms with major depression disorder and treatment response to antidepressants in a Han Chinese population. Gen Hosp Psychiatry. 2012, 34: 571-577. 10.1016/j.genhosppsych.2012.05.015. Cui DH, Jiang KD, Jiang SD, Xu YF, Yao H: The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia. Mol Psychiatry. 2005, 10: 669-677. 10.1038/sj.mp.4001653. Fodde R, Smits R: Disease model: familial adenomatous polyposis. Trends Mol Med. 2001, 7: 369-373. 10.1016/S1471-4914(01)02050-0. Koshimizu H, Fukui Y, Takao K, Ohira K, Tanda K, Nakanishi K, Toyama K, Oshima M, Taketo MM, Miyakawa T: Adenomatous polyposis coli heterozygous knockout mice display hypoactivity and age-dependent working memory deficits. Front Behav Neurosci. 2011, 5: 85- Smits R, Kielman MF, Breukel C, Zurcher C, Neufeld K, Jagmohan-Changur S, Hofland N, van Dijk J, White R, Edelmann W, Kucherlapati R, Khan PM, Fodde R: Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. Genes Dev. 1999, 13: 1309-1321. 10.1101/gad.13.10.1309. Chen G, Wang LP, Tsien JZ: Neural population-level memory traces in the mouse hippocampus. PLoS One. 2009, 4: e8256-10.1371/journal.pone.0008256. Remington G: Alterations of dopamine and serotonin transmission in schizophrenia. Prog Brain Res. 2008, 172: 117-140. Nakatani-Pawlak A, Yamaguchi K, Tatsumi Y, Mizoguchi H, Yoneda Y: Neonatal phencyclidine treatment in mice induces behavioral, histological and neurochemical abnormalities in adulthood. Biol Pharm Bull. 2009, 32: 1576-1583. 10.1248/bpb.32.1576. Oyagi A, Oida Y, Kakefuda K, Shimazawa M, Shioda N, Moriguchi S, Kitaichi K, Nanba D, Yamaguchi K, Furuta Y, Fukunaga K, Higashiyama S, Hara H: Generation and characterization of conditional heparin-binding EGF-like growth factor knockout mice. PLoS One. 2009, 4: e7461-10.1371/journal.pone.0007461. Takao K, Kobayashi K, Hagihara H, Ohira K, Shoji H, Hattori S, Koshimizu H, Umemori J, Toyama K, Nakamura HK, Kuroiwa M, Maeda J, Atsuzawa K, Esaki K, Yamaguchi S, Furuya S, Takagi T, Walton NM, Hayashi N, Suzuki H, Higuchi M, Usuda N, Suhara T, Nishi A, Matsumoto M, Ishii S, Miyakawa T: Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia. Neuropsychopharmacology. 2013, 38: 1409-1425. 10.1038/npp.2013.38. Takao K, Yamasaki N, Miyakawa T: Impact of brain-behavior phenotypying of genetically-engineered mice on research of neuropsychiatric disorders. Neurosci Res. 2007, 58: 124-132. 10.1016/j.neures.2007.02.009. Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC: Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci U S A. 2008, 105: 5585-5590. 10.1073/pnas.0710373105. Wiedholz LM, Owens WA, Horton RE, Feyder M, Karlsson RM, Hefner K, Sprengel R, Celikel T, Daws LC, Holmes A: Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and ‘schizophrenia-related’ behaviors. Mol Psychiatry. 2008, 13: 631-640. 10.1038/sj.mp.4002056. Yamasaki N, Maekawa M, Kobayashi K, Kajii Y, Maeda J, Soma M, Takao K, Tanda K, Ohira K, Toyama K, Kanzaki K, Fukunaga K, Sudo Y, Ichinose H, Ikeda M, Iwata N, Ozaki N, Suzuki H, Higuchi M, Suhara T, Yuasa S, Miyakawa T: Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders. Mol Brain. 2008, 1: 6-10.1186/1756-6606-1-6. Kellendonk C, Simpson EH, Kandel ER: Modeling cognitive endophenotypes of schizophrenia in mice. Trends Neurosci. 2009, 32: 347-358. 10.1016/j.tins.2009.02.003. Lewis DA, Gonzalez-Burgos G: Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology. 2008, 33: 141-165. 10.1038/sj.npp.1301563. Barros CS, Calabrese B, Chamero P, Roberts AJ, Korzus E, Lloyd K, Stowers L, Mayford M, Halpain S, Muller U: Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system. Proc Natl Acad Sci U S A. 2009, 106: 4507-4512. 10.1073/pnas.0900355106. 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: Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. J Neurosci. 2008, 28: 6872-6883. 10.1523/JNEUROSCI.1815-08.2008. Sudhof TC: Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008, 455: 903-911. 10.1038/nature07456. Chen Y, Bourne J, Pieribone VA, Fitzsimonds RM: The role of actin in the regulation of dendritic spine morphology and bidirectional synaptic plasticity. Neuroreport. 2004, 15: 829-832. 10.1097/00001756-200404090-00018. Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC: Storage of spatial information by the maintenance mechanism of LTP. Science. 2006, 313: 1141-1144. 10.1126/science.1128657. Tamminga CA, Stan AD, Wagner AD: The hippocampal formation in schizophrenia. Am J Psychiatr. 2010, 167: 1178-1193. 10.1176/appi.ajp.2010.09081187. Meyer-Lindenberg AS, Olsen RK, Kohn PD, Brown T, Egan MF, Weinberger DR, Berman KF: Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch Gen Psychiatry. 2005, 62: 379-386. 10.1001/archpsyc.62.4.379. Henseler I, Falkai P, Gruber O: A systematic fMRI investigation of the brain systems subserving different working memory components in schizophrenia. Eur J Neurosci. 2009, 30: 693-702. 10.1111/j.1460-9568.2009.06850.x. Eisenberg DP, Ianni AM, Wei SM, Kohn PD, Kolachana B, Apud J, Weinberger DR, Berman KF: Brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism differentially predicts hippocampal function in medication-free patients with schizophrenia. Mol Psychiatry. 2013, 18: 713-720. 10.1038/mp.2012.187. Manoach DS: Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophr Res. 2003, 60: 285-298. Snyder MA, Gao WJ: NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia. Front Cell Neurosci. 2013, 7: 31- Kornau HC, Schenker LT, Kennedy MB, Seeburg PH: Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science. 1995, 269: 1737-1740. 10.1126/science.7569905. Shimomura A, Ohkuma M, Iizuka-Kogo A, Kohu K, Nomura R, Miyachi E, Akiyama T, Senda T: Requirement of the tumour suppressor APC for the clustering of PSD-95 and AMPA receptors in hippocampal neurons. Eur J Neurosci. 2007, 26: 903-912. 10.1111/j.1460-9568.2007.05723.x. Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, Caron MG, Tonegawa S: Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc Natl Acad Sci U S A. 2003, 100: 8987-8992. 10.1073/pnas.1432926100. Izzo PN, Graybiel AM, Bolam JP: Characterization of substance P- and [Met]enkephalin-immunoreactive neurons in the caudate nucleus of cat and ferret by a single section Golgi procedure. Neuroscience. 1987, 20: 577-587. 10.1016/0306-4522(87)90111-4. Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976, 72: 248-254. 10.1016/0003-2697(76)90527-3.
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Molecular Brain

Tập 7

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