Fyn遺伝子と動物行動

• 研究課題/領域番号: 12053269
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 大阪大学
• 研究代表者: 八木 健 大阪大学, 大学院・生命機能研究科, 教授 (10241241)
• 研究期間 (年度): 2000 – 2004
• 研究課題ステータス: 完了 (2004年度)
• 配分額: 54,500千円 (直接経費: 54,500千円); 2004年度: 10,500千円 (直接経費: 10,500千円); 2003年度: 10,800千円 (直接経費: 10,800千円); 2002年度: 11,000千円 (直接経費: 11,000千円); 2001年度: 11,400千円 (直接経費: 11,400千円); 2000年度: 10,800千円 (直接経費: 10,800千円)
• キーワード: Fyn / CNR / プロトカドヘリン / カドヘリン / 行動 / 脳 / ゲノム / 心 / 行動学 / 遺伝学 / 神経科学 / 脳・神経 / リーリン / 情動行動 / 遺伝子クラスター / 多様化 / シナプス / 神経回路形成

研究概要

本研究では、動物行動を制御する遺伝子としてFynに注目し解析を行ってきた。Fyn欠損マウスは、ほ乳行動異常が認められており、Fyn欠損母マウスはFyn欠損子マウスにミルクを与えることができず死亡する。この死亡の原因には、環境因子が想定されていたが、本研究により飼育環境のヘキサナールの影響を明らかにした。Fyn欠損母マウスでは、ほ乳行動の巣作り行動等に異常があり、ヘキサナールによる効果が重なりあうことにより、子の死亡が起こったことが明らかとなった。また、ヘキサナールにより活性化される脳領域の解析をc-fos発現活性を利用して行った結果、Fyn欠損雌マウスの脳では、ヘキサナールにより視床下部のMedial preoptic area (MPOA)が異常に活性化されていた。このMPOAは正常雌マウスにおいて子マウス存在下でc-fos発現の活性化が引き起こされる領域である。また、このMPOAの異常な活性化は扁桃体の領域でも起こっており、Fyn欠損マウスでは扁桃体における神経回路が異常となっていることが明らかとなった。Fyn欠損マウスでは、恐がりとなる情動性の異常が認められている。これらの結果は、Fynがほ乳動物における認識機構や情動性制御に関わっていることを示すものである。ヒトにおいては、不安や恐怖などの情動性、環境の認識に関わる精神神経疾患が知られており、Fynのヒト精神神経疾患との関わりについても興味がもたれる。

研究成果

• [雑誌論文] Monoallelic yet combinatorial expression of variable exons of the CNR/Protocadherin-α gene cluster in single neurons (2005)
  • 著者名/発表者名: Esumi S, Kakazu N, Taguchi Y, Hirayama T, Sasaki A, Hirabayashi T, Koide T, Kitsukawa T, Hamada S, Yagi T
  • 雑誌名: Nature Genet. 37(2) ページ: 171-176
• [雑誌論文] Monoallelic yet combinatorial expression of variable exons of the CNR/Protocadherin-α gene cluster in single neurons (2005)
  • 著者名/発表者名: Miki R, Hattori K, Taguchi Y, Tada M, Isosaka T, Hidaka Y, Hirabayashi T, Hashimoto R, Fukuzako H, Yagi T
  • 雑誌名: GENE (印刷中)
• [雑誌論文] A Novel Function of Neuronal PAS Domain Protein 1 (NPAS1) in Erythropoietin Expression in Neuronal Cells (2005)
  • 著者名/発表者名: Ohsawa S, Hamada S, Kakinuma Y, Yagi T, Miura M
  • 雑誌名: J.Neurosci.Res. 79 ページ: 451-458
• [雑誌論文] Myelination triggers local loss of axonal CNR/Protocadherin α family protein expression (2004)
  • 著者名/発表者名: Morishita H, Kawaguchi M, Murata Y, Seiwa C, Hamada S, Asou H, Yagi T
  • 雑誌名: Eur.J, Neurosci. 20 ページ: 2843-2847
• [雑誌論文] CNR/Pcdh α family in subplate neurons, and developing cortical connectivity (2004)
  • 著者名/発表者名: Morishita H, Murata Y, Esumi S, Hamada S, Yagi T
  • 雑誌名: Neuroreport 15(17) ページ: 2595-2599
• [雑誌論文] Auditory-conditioned-fear-dependent c-Fos expression is altered in the emotion-related brain structures of Fyn-deficient mice (2004)
  • 著者名/発表者名: Kubota O, Hattor K, Hashimoto K, Yagi T, Sato T, Iyo M, Yuasa S
  • 雑誌名: Mol.Brain Res. 130 ページ: 149-160
• [雑誌論文] Interaction with Protocadherin-γ regulates the cell-surface expression of Protocadherin-α (2004)
  • 著者名/発表者名: Murata Y, Hamada S, Morishita H, Mutoh T, Yagi T
  • 雑誌名: J.Biol.Chem. 279(47) ページ: 49508-49516
• [雑誌論文] NMDA receptor GluRepsilon/NR2 subunits are essentil for postsynaptic localization and protein stability of GluRzeta 1/NR1 subunit (2004)
  • 著者名/発表者名: Abe M, Fukuya M, Yagi T, Mishina M, Watanabe M, Sakimura K
  • 雑誌名: J.Neuroscei. 24(33) ページ: 9292-9304
• [雑誌論文] Genomic organization and transcripts of the zebrafish Protocadherin genes (2004)
  • 著者名/発表者名: Tada T, Senzaki K, Tai Y, Morishita H, Tanaka Y, Murata Y, Ishii Y, Asakawa S, Shimizu N, Sugino H, Yagi T
  • 雑誌名: Gene 340 ページ: 197-211
• [雑誌論文] Exposure to hexanal odor induces extraordinary Fos expression in the medial preoptic area and amygdala of Fyn tyrosine kinase-deficient mice (2004)
  • 著者名/発表者名: Hamaguchi-Hamada K, Hamada S, Yagi T
  • 雑誌名: Mol.Brain Res. 130(1-2) ページ: 187-190
• [雑誌論文] Construction of BAC library for the amphibian, Xenopus tropicalis (2004)
  • 著者名/発表者名: Ishi Y, Asakawa S, Taguchi Y, Ishibashi S, Yagi T, Shimizu N.
  • 雑誌名: Genes & Genetic Systems 79 ページ: 49-51
  • NAID: 10012907202
• [雑誌論文] Defective neocortical development in Fyn-tyrosine-kinase-deficient mice (2004)
  • 著者名/発表者名: Yuasa S, Hattori K, Yagi T
  • 雑誌名: Neuroreport 15(5) ページ: 819-822
• [文献書誌] Sugino H, Yanase H, Hamada S, Kurokawa K, Asakawa S, Shimizu N, Yagi T.: "Distinct genomic sequence of the CNR/Pcdh α genes in chiken"Biochemical and Biophysical Research Communications. 316. 437-445 (2004)
• [文献書誌] Yuasa S, Hattori K, Yagi T: "Defective neocortical development in Fyn-tyrosine-kinase-deficient mice"Neuro Report. in press. (2004)
• [文献書誌] Mutoh T, Hamada S, Yagi T: "Cadherin-related Neuronal Receptor 1(CNR1) has cell-adhesion activity with β1 integrin mediated through the RGD site of CNR1"Experimental Cell Research. in press. (2004)
• [文献書誌] Sugino H, Miyazak M, Yagi T: "Intron-less processed cadherin-related neuronal receptor (CNR/Pcdha) genes in the central nervous system"Biochemical and Biophysical Research Communications. 313. 775-783 (2004)
• [文献書誌] Hamaguchi-Hamada K, Sanbo C, Hamada S, Yagi T: "Exposure to hexanal odor influences maternal behavior and induces neonatal death in Fyn tyrosine kinase-deficient mice"Neurosci.Res.. in press. (2004)
• [文献書誌] Yanase H, Sugino H, Yagi T: "Genomic sequence and organization of the family of CNR/Pcdh α genes in Rat"Genomics. in press. (2004)
• [文献書誌] Nakahara J, Tan-Takeuchi K, Seiwa C, Gotoh M, Kaifu T, Ujike A, Inui M, Yagi T, Ogawa M, Aiso S, Takai T, Asou H: "Signaling via Immunoglobulin Fc Receptors Induces Oligodendrocyte Precursor Cell Differentiation"Developmental Cell. 4. 841-852 (2003)
• [文献書誌] Cowen MS, Schumann G, Yagi T, Spanagel R.: "Role of Fyn tyrosine kinase in ethanol consumption by mice."Alcohol Clin Exp Res.. Aug;27(8). 1213-1239 (2003)
• [文献書誌] Masuda T, Tsuji H, Taniguchi M, Yagi T, Tessier-Lavigne M, Fujisawa H, Okado N, Shiga T.: "Differential non-target-derived repulsive signals play a critical role in shaping initial axonal growth of dorsal root ganglion neurons."Developmental Biology. 15;254(2). 289-302 (2003)
• [文献書誌] 服部功太郎, 湯浅茂樹, 八木 健: "Fyn関連遺伝子による大脳皮質形成機構"蛋白質核酸酵素. 49;3. 425-430 (2004)
• [文献書誌] Taniguchi M, Nagao H, Takahashi Y, Yamaguchi M, Mitsui S, Yagi T, Mori K, Shimizu T: "Distorted Odor Maps in the Olfactory Bulb of Semaphorin 3A-Deficient Mice"The Journal of Neuroscience. 23(4)(in press). (2003)
• [文献書誌] Yagi T: "Diversity of the cadherin-related neuronal receptor/protocadherin family and possible DNA rearrangement in the brain"Genes to Cells. 8. 1-8 (2003)
• [文献書誌] Fukumoto E, Sakai H, Fukumoto S, Yagi T, Takagi O, Kato Y: "Cadherin-related Neuronal Receptors in Incisor Development"Journal of Dental Research. 82(1). 17-22 (2003)
• [文献書誌] Yagi T, Tada M, Tanaka Y, Senzaki K, Hirayama T, Hamada S, Sugino H: "Diversity of the cadherin-related neuronal receptor family in the nervous system""Genome Science-Towards a New Paradigm?" : International Cpngress Series. 1246. 127-136 (2002)
• [文献書誌] Yasuda K, Nagafuku M, Shima T, Okada M, Yagi T, Yamada T, Minami Y, Kato a, Tani-Ichi S, Hamaoka t, Kosugi A: "Cutting edge : Fyn is essential for tyrosinase phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells"The Journal of Immunology. 169(6). 2813-2817 (2002)
• [文献書誌] Kanda H, Igaki T, Kanuka H, Yagi T, Miura M: "Wengen, a member of the Drosophila TNF receptor superfamily, is required for Eiger signaling"The Journal of Biological Chemistry. 277(32). 28372-28375 (2002)
• [文献書誌] Maekawa M, Toyama Y, Yasda M, Yagi T, Yuasa S: "Fyn Tyrosinase in Sertoki Cells Is Involved in Mouse Spermatogenesis"Biology of Reproductions. 66. 211-221 (2002)
• [文献書誌] Sasaki Y, Cheng C, Uchida Y, Nakajima O, Oshima T, Yagi T, Taniguchi M, Nakayama T, Kishida R, Kudo Y, Ohno S, Nakamura F, Goshima Y: "Fyn and Cdk5 Mediate Semaphorin-3A Signaling, Which is Involved in Regulation of Dendrite Orientation in Cerebral Cortex"Neuron. 35. 907-920 (2002)
• [文献書誌] Kawasaki T, Bekku Y, Suto F.Kitsukawa T.Taniguchi M.Nagatsu I, Nagatsu T, Itoh K, Yagi T, Fujisawa H: "Requirement of neuropilin 1-mediated Sema3A signals in patterning of the sympathetic nervous system"Development. 129. 671-680 (2002)
• [文献書誌] Hirayama T, Sugino H, Yagi T: "Somatic mutations of synaptic cadherin (CNR family) transcripts in the nervous system"Genes to Cells. 6(2). 151-164 (2001)
• [文献書誌] Nakahara J, Tan-Takeuchi K, Seiwa C, Yagi T, Aiso S, Kawamura K, Asou H.: "Related Articles Myelin basic protein is necessary for the regulation of myelin-associated glycoprotein expression in mouse oligodendroglia"Neurosci Lett.. 298. 163-166 (2001)
• [文献書誌] Nakamura K, Manabe T, Watanabe M, Mamiya T, Ichikawa R, Kiyama Y, Sanbo M, Yagi T, Inoue Y, Nabeshima T, Mori H, Mishina M: "Related Articles Enhancement of hippocampal LTP, reference memory and sensorimotor gating in mutant mice lacking a telencephalon-specific cell adhesion molecule"Eur.J.Neurosci.. 13. 179-189 (2001)
• [文献書誌] Takei Y, Hamada S, Senzaki K, Mutoh T, Sugino H, Yagi T: "Two novel CNRs from the CNR gene cluster have molecular features distinct from those of CNR1 to 8"Genomics. 72. 321-330 (2001)
• [文献書誌] Miyakawa T, Yagi T, Takao K, Niki H: "Differential effect of Fyn tyrosine kinase deletion on offensive and defensive aggression"Mol.Brain Res.. 122. 51-56 (2001)
• [文献書誌] Hoffmn PL, Yagi T, Tabakoff B, Phillips TJ, Kono H, Messing RO, Choi D-S: "Transgenic and gene "knockout" models in alcohol research"Alcohol Clin.Exp.Res.. 25. 60S-66S (2001)
• [文献書誌] Sugimoto Y, Taniguchi M, Yagi T, Akagi Y, Nojyo Y, Tamamaki N: "Guidance of glial precursor cell migration by secreted cues in the developing optic nerve"Development. 128. 3321-3330 (2001)
• [文献書誌] Hattori K, Yagi T, Maekawa M, Sato T, Yuasa S: "Related Articles N-Methyl-D-aspartate-induced c-Fos expression is enhanced in the forebrain structures related to emotion in Fyn-deficient mice"Brain Res.. 905. 188-198 (2001)
• [文献書誌] Hamada S, Yagi T: "The cadherin-related neuronal receptor (CNR) family : a novel diversified cadherin family at the synapse"Neuroscience Res.. 41. 207-215 (2001)
• [文献書誌] Shima T, Okumura N, Takao T, Satomi Y, Yagi T, Okada M, Nagai K: "Interaction of the SH2 domain of Fyn with a cytoskeletal protein, beta-aducin"J.Biol.Chem.. 276. 42233-42240 (2001)
• [文献書誌] Yamazaki Y, Makino H, Hamaguchi-Hamada K, Hamada S, Sigino H, Kawase E, Miyata T, Ogawa M, Yanagimachi R, Yagi T: "Assessment of the developmental totipotency of neural cells in the cerebral cortex of mouse embryo by nuclear transfer"Proc.Natl.Acad.Sci.USA. 98. 14022-14026 (2001)
• [文献書誌] Sugino H.: "Genomic organization of the family of CNR cadherin genes in mice and humans."Genomics. 63. 75-87 (2000)
• [文献書誌] Yamazaki Y.: "In vivo gene transfer to mouse spermatogenic cells using green fluorescent protein as a marker."Journal of Experimental Zoology. 286. 212-218 (2000)
• [文献書誌] Yagi T.: "Cadherin superfamily genes : functions, genomic organization, and neurologic diversity."Genes & Development. 14. 1169-1180 (2000)
• [文献書誌] Shima Y.: "Changes in circadian period and morphology of the hypothalamic suprachiasmatic nucleus in fyn kinase-deficient mice."Brain Research. 870. 36-43 (2000)
• [文献書誌] Kitazawa H.: "Dynamic characteristics and adaptability of reflex eye movements of Fyn kinase-deficient mice."Neuroscience Letter. 280. 179-182 (2000)
• [文献書誌] Seiwa C.: "Fyn tyrosine kinase participates in the compact myelin sheath central nervous system."Neuroscience Research. 37. 21-31 (2000)
• [文献書誌] Huang G-Z.: "Involvement of complexin II in synaptic plasticity in the CA1 region of the hippocampus : The use of complexin II-lacking mice."Japan Journal Pharmacology. 84. 179-187 (2000)
• [文献書誌] Kawase E.: "Mouse embryonic stem (ES) cell lines established from neuronal cell-derived cloned blastocysts."Genesis. 28. 156-163 (2000)
• [文献書誌] Mei Z-t.: "Impairment of conditioned avoidance response in Fyn-kinase deficient mice."China Journal Neuroscience. 16. 293-298 (2000)
• [文献書誌] Hirayama T.: "Somatic mutations of synaptic cadherin (CNR family) transcripts in the nervous system."Genes to Cells,. (in press). (2001)
• [文献書誌] Miyakawa T.: "Differential effect of Fyn tyrosine kinase deletion on offensive and defensive aggression."Molecular Brain Research,. (in press). (2001)
• [文献書誌] Yagi T.: "Ethanol sensitivity and molecular function of Fyn tyrosine kinase. "Ethanol and Intracellular signalling : From Molecules to Behavior""CSR incorporated,in Washington,DC.. (2001)
• [文献書誌] Takei Y.: "Two novel CNRs from the CNR gene cluster have molecular features distinct from those of CNR1 to 8"Genomics,. 73(in press). (2001)
• [文献書誌] Nakahara J.: "Myelin basic protein is necessary for the regulation of myelin-associated glycoprotein expression in mouse oligodendroglia."Neuroscience Letter. 298(3). 163-166 (2001)
• [文献書誌] Nakamura K.: "Enhancement of hippocampal LTP, reference memory and sensorimotor gating in mutant mice lacking a telencephalon-specific cell adhesion molecule."Euro Journal Neuroscience. 13(1). 179-189 (2001)
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