Fyn遺伝子と動物行動

• Project/Area Number: 12053269
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University
• Principal Investigator: 八木 健 大阪大学, 大学院・生命機能研究科, 教授 (10241241)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥54,500,000 (Direct Cost: ¥54,500,000); Fiscal Year 2004: ¥10,500,000 (Direct Cost: ¥10,500,000); Fiscal Year 2003: ¥10,800,000 (Direct Cost: ¥10,800,000); Fiscal Year 2002: ¥11,000,000 (Direct Cost: ¥11,000,000); Fiscal Year 2001: ¥11,400,000 (Direct Cost: ¥11,400,000); Fiscal Year 2000: ¥10,800,000 (Direct Cost: ¥10,800,000)
• Keywords: 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

Research Abstract

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。

Research Products

• [Journal Article] Monoallelic yet combinatorial expression of variable exons of the CNR/Protocadherin-α gene cluster in single neurons (2005)
  • Author(s): Esumi S, Kakazu N, Taguchi Y, Hirayama T, Sasaki A, Hirabayashi T, Koide T, Kitsukawa T, Hamada S, Yagi T
  • Journal Title: Nature Genet. 37(2) Pages: 171-176
• [Journal Article] Monoallelic yet combinatorial expression of variable exons of the CNR/Protocadherin-α gene cluster in single neurons (2005)
  • Author(s): Miki R, Hattori K, Taguchi Y, Tada M, Isosaka T, Hidaka Y, Hirabayashi T, Hashimoto R, Fukuzako H, Yagi T
  • Journal Title: GENE (印刷中)
• [Journal Article] A Novel Function of Neuronal PAS Domain Protein 1 (NPAS1) in Erythropoietin Expression in Neuronal Cells (2005)
  • Author(s): Ohsawa S, Hamada S, Kakinuma Y, Yagi T, Miura M
  • Journal Title: J.Neurosci.Res. 79 Pages: 451-458
• [Journal Article] Myelination triggers local loss of axonal CNR/Protocadherin α family protein expression (2004)
  • Author(s): Morishita H, Kawaguchi M, Murata Y, Seiwa C, Hamada S, Asou H, Yagi T
  • Journal Title: Eur.J, Neurosci. 20 Pages: 2843-2847
• [Journal Article] CNR/Pcdh α family in subplate neurons, and developing cortical connectivity (2004)
  • Author(s): Morishita H, Murata Y, Esumi S, Hamada S, Yagi T
  • Journal Title: Neuroreport 15(17) Pages: 2595-2599
• [Journal Article] Auditory-conditioned-fear-dependent c-Fos expression is altered in the emotion-related brain structures of Fyn-deficient mice (2004)
  • Author(s): Kubota O, Hattor K, Hashimoto K, Yagi T, Sato T, Iyo M, Yuasa S
  • Journal Title: Mol.Brain Res. 130 Pages: 149-160
• [Journal Article] Interaction with Protocadherin-γ regulates the cell-surface expression of Protocadherin-α (2004)
  • Author(s): Murata Y, Hamada S, Morishita H, Mutoh T, Yagi T
  • Journal Title: J.Biol.Chem. 279(47) Pages: 49508-49516
• [Journal Article] NMDA receptor GluRepsilon/NR2 subunits are essentil for postsynaptic localization and protein stability of GluRzeta 1/NR1 subunit (2004)
  • Author(s): Abe M, Fukuya M, Yagi T, Mishina M, Watanabe M, Sakimura K
  • Journal Title: J.Neuroscei. 24(33) Pages: 9292-9304
• [Journal Article] Genomic organization and transcripts of the zebrafish Protocadherin genes (2004)
  • Author(s): Tada T, Senzaki K, Tai Y, Morishita H, Tanaka Y, Murata Y, Ishii Y, Asakawa S, Shimizu N, Sugino H, Yagi T
  • Journal Title: Gene 340 Pages: 197-211
• [Journal Article] Exposure to hexanal odor induces extraordinary Fos expression in the medial preoptic area and amygdala of Fyn tyrosine kinase-deficient mice (2004)
  • Author(s): Hamaguchi-Hamada K, Hamada S, Yagi T
  • Journal Title: Mol.Brain Res. 130(1-2) Pages: 187-190
• [Journal Article] Construction of BAC library for the amphibian, Xenopus tropicalis (2004)
  • Author(s): Ishi Y, Asakawa S, Taguchi Y, Ishibashi S, Yagi T, Shimizu N.
  • Journal Title: Genes & Genetic Systems 79 Pages: 49-51
  • NAID: 10012907202
• [Journal Article] Defective neocortical development in Fyn-tyrosine-kinase-deficient mice (2004)
  • Author(s): Yuasa S, Hattori K, Yagi T
  • Journal Title: Neuroreport 15(5) Pages: 819-822
• [Publications] 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)
• [Publications] Yuasa S, Hattori K, Yagi T: "Defective neocortical development in Fyn-tyrosine-kinase-deficient mice"Neuro Report. in press. (2004)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] Yanase H, Sugino H, Yagi T: "Genomic sequence and organization of the family of CNR/Pcdh α genes in Rat"Genomics. in press. (2004)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] Sugino H.: "Genomic organization of the family of CNR cadherin genes in mice and humans."Genomics. 63. 75-87 (2000)
• [Publications] 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)
• [Publications] Yagi T.: "Cadherin superfamily genes : functions, genomic organization, and neurologic diversity."Genes & Development. 14. 1169-1180 (2000)
• [Publications] Shima Y.: "Changes in circadian period and morphology of the hypothalamic suprachiasmatic nucleus in fyn kinase-deficient mice."Brain Research. 870. 36-43 (2000)
• [Publications] Kitazawa H.: "Dynamic characteristics and adaptability of reflex eye movements of Fyn kinase-deficient mice."Neuroscience Letter. 280. 179-182 (2000)
• [Publications] Seiwa C.: "Fyn tyrosine kinase participates in the compact myelin sheath central nervous system."Neuroscience Research. 37. 21-31 (2000)
• [Publications] 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)
• [Publications] Kawase E.: "Mouse embryonic stem (ES) cell lines established from neuronal cell-derived cloned blastocysts."Genesis. 28. 156-163 (2000)
• [Publications] Mei Z-t.: "Impairment of conditioned avoidance response in Fyn-kinase deficient mice."China Journal Neuroscience. 16. 293-298 (2000)
• [Publications] Hirayama T.: "Somatic mutations of synaptic cadherin (CNR family) transcripts in the nervous system."Genes to Cells,. (in press). (2001)
• [Publications] Miyakawa T.: "Differential effect of Fyn tyrosine kinase deletion on offensive and defensive aggression."Molecular Brain Research,. (in press). (2001)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 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)
• [Publications] 八木健: "ジーンターゲティングの最新技術"羊土社. 233 (2000)