PAX遺伝子群

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2012年10月30日 (火) 19:22時点におけるNosumi (トーク | 投稿記録)による版

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英：Paired box (Pax) genes

　Pax遺伝子群は動物の胎生期に、組織や器官の発生において中心的な役割を果たす遺伝子ファミリーである。脊椎動物ではPax1〜Pax9の9種類が同定されている(図)。Pax遺伝子群は DNA結合ドメインであるペアードドメイン(PD)と呼ばれる領域を共通に持っている。また、Pax遺伝子にはオクタペプチドモチーフ（OP）を持つものや、DNA結合ドメインであるホメオドメイン、もしくはホメオドメインの一部を持つものがある。このような遺伝子配列の違いから、Pax遺伝子群は4つのサブファミリーに分類される。 Pax遺伝子群はヒトやマウスに於いて、病気の原因遺伝子として同定されたものが多い。例えば、眼の発生のマスター制御遺伝子であるPAX6は、無虹彩症の原因遺伝子である。

胎生期および生後の神経系におけるPax遺伝子群の発現パターン

詳細は図およびAllen Brain Atlas[[1]]を参照にされたい。特にPax6は、神経板期（数体節期：マウスE8.5）に、前脳区画および前耳溝以後の菱脳・脊髄で発現が開始する。神経管閉鎖後、脳胞期（約30体節期: マウスE10.5）には、終脳背側（将来の大脳皮質領域）、間脳背側（将来の腹側・背側視床）、菱脳・脊髄の腹外側で発現する。生後も脳室層、扁桃体、視床、海馬、小脳、下垂体などで発現が見られる。中枢神経系以外では、水晶体、角膜上皮、網膜神経上皮、嗅上皮、膵臓に発現している。

神経系の発生におけるPax遺伝子群の機能

　Pax遺伝子群は他の転写遺伝子と協調し、神経系の発生初期では細胞の運命決定や脳の領域化 [1][2][3][4][5][6]、発生後期では細胞増殖、細胞移動、細胞分化に関わっている[7][8][9][10][11][12][13]。Pax遺伝子群の発現は胎生期において認められるだけではなく、生後および成体脳においても認められる[2][10][11][14][15][16][17][18][19][20]。

脳の領域化、細胞の運命決定におけるPax遺伝子群の機能

Pax遺伝子群の発現は、神経板の形成などの神経発生初期から始まる。神経発生の初期では、シグナルセンターからの情報によって、前後軸、背腹軸が決定され、脳の領域化が起こる[21][22]。Pax遺伝子群はシグナルセンターから放出されるシグナル分子に反応し[1][23][24][25][26][27][28][29]、脳の領域化や細胞の運命決定に寄与することがわかっている[2][4][7][30][31]。Pax6は、菱脳・脊髄における運動ニューロン・介在ニューロン分化に関して、classI HDタンパクとclassII HDタンパクとの間に正確な境界形成を行うことを通じて菱脳腹側の区画化を制御する[32]。その他Pax6には、前脳のコンパートメント形成、神経路形成（後交連、TPOC、嗅索、視床皮質路）、終脳背側ニューロン分化、小脳顆粒細胞の形成など多岐にわたる役割がある。


  1. ↑ 1.0 1.1 Ericson, J., Rashbass, P., Schedl, A., Brenner-Morton, S., Kawakami, A., van Heyningen, V., ..., & Briscoe, J. (1997).
    Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling. Cell, 90(1), 169-80. [PubMed:9230312] [WorldCat] [DOI]
  2. ↑ 2.0 2.1 2.2 Kawakami, A., Kimura-Kawakami, M., Nomura, T., & Fujisawa, H. (1997).
    Distributions of PAX6 and PAX7 proteins suggest their involvement in both early and late phases of chick brain development. Mechanisms of development, 66(1-2), 119-30. [PubMed:9376315] [WorldCat] [DOI]
  3. ↑ Matsunaga, E., Araki, I., & Nakamura, H. (2000).
    Pax6 defines the di-mesencephalic boundary by repressing En1 and Pax2. Development (Cambridge, England), 127(11), 2357-65. [PubMed:10804178] [WorldCat]
  4. ↑ 4.0 4.1 Nomura, T., Kawakami, A., & Fujisawa, H. (1998).
    Correlation between tectum formation and expression of two PAX family genes, PAX7 and PAX6, in avian brains. Development, growth & differentiation, 40(5), 485-95. [PubMed:9783474] [WorldCat]
  5. ↑ Schwarz, M., Cecconi, F., Bernier, G., Andrejewski, N., Kammandel, B., Wagner, M., & Gruss, P. (2000).
    Spatial specification of mammalian eye territories by reciprocal transcriptional repression of Pax2 and Pax6. Development (Cambridge, England), 127(20), 4325-34. [PubMed:11003833] [WorldCat]
  6. ↑ Stoykova, A., & Gruss, P. (1994).
    Roles of Pax-genes in developing and adult brain as suggested by expression patterns. The Journal of neuroscience : the official journal of the Society for Neuroscience, 14(3 Pt 2), 1395-412. [PubMed:8126546] [WorldCat]
  7. ↑ 7.0 7.1 Burrill, J.D., Moran, L., Goulding, M.D., & Saueressig, H. (1997).
    PAX2 is expressed in multiple spinal cord interneurons, including a population of EN1+ interneurons that require PAX6 for their development. Development (Cambridge, England), 124(22), 4493-503. [PubMed:9409667] [WorldCat]
  8. ↑ Chan-Ling, T., Chu, Y., Baxter, L., Weible Ii, M., & Hughes, S. (2009).
    In vivo characterization of astrocyte precursor cells (APCs) and astrocytes in developing rat retinae: differentiation, proliferation, and apoptosis. Glia, 57(1), 39-53. [PubMed:18661555] [WorldCat] [DOI]
  9. ↑ Conway, S.J., Bundy, J., Chen, J., Dickman, E., Rogers, R., & Will, B.M. (2000).
    Decreased neural crest stem cell expansion is responsible for the conotruncal heart defects within the splotch (Sp(2H))/Pax3 mouse mutant. Cardiovascular research, 47(2), 314-28. [PubMed:10946068] [WorldCat] [DOI]
  10. ↑ 10.0 10.1 Kohwi, M., Osumi, N., Rubenstein, J.L., & Alvarez-Buylla, A. (2005).
    Pax6 is required for making specific subpopulations of granule and periglomerular neurons in the olfactory bulb. The Journal of neuroscience : the official journal of the Society for Neuroscience, 25(30), 6997-7003. [PubMed:16049175] [PMC] [WorldCat] [DOI]
  11. ↑ 11.0 11.1 Maekawa, M., Takashima, N., Arai, Y., Nomura, T., Inokuchi, K., Yuasa, S., & Osumi, N. (2005).
    Pax6 is required for production and maintenance of progenitor cells in postnatal hippocampal neurogenesis. Genes to cells : devoted to molecular & cellular mechanisms, 10(10), 1001-14. [PubMed:16164600] [WorldCat] [DOI]
  12. ↑ Marquardt, T., Ashery-Padan, R., Andrejewski, N., Scardigli, R., Guillemot, F., & Gruss, P. (2001).
    Pax6 is required for the multipotent state of retinal progenitor cells. Cell, 105(1), 43-55. [PubMed:11301001] [WorldCat] [DOI]
  13. ↑ Talamillo, A., Quinn, J.C., Collinson, J.M., Caric, D., Price, D.J., West, J.D., & Hill, R.E. (2003).
    Pax6 regulates regional development and neuronal migration in the cerebral cortex. Developmental biology, 255(1), 151-63. [PubMed:12618140] [WorldCat] [DOI]
  14. ↑ Hack, M.A., Saghatelyan, A., de Chevigny, A., Pfeifer, A., Ashery-Padan, R., Lledo, P.M., & Götz, M. (2005).
    Neuronal fate determinants of adult olfactory bulb neurogenesis. Nature neuroscience, 8(7), 865-72. [PubMed:15951811] [WorldCat] [DOI]
  15. ↑ Kukekov, V.G., Laywell, E.D., Suslov, O., Davies, K., Scheffler, B., Thomas, L.B., ..., & Steindler, D.A. (1999).
    Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain. Experimental neurology, 156(2), 333-44. [PubMed:10328940] [WorldCat] [DOI]
  16. ↑ Nacher, J., Varea, E., Blasco-Ibañez, J.M., Castillo-Gomez, E., Crespo, C., Martinez-Guijarro, F.J., & McEwen, B.S. (2005).
    Expression of the transcription factor Pax 6 in the adult rat dentate gyrus. Journal of neuroscience research, 81(6), 753-61. [PubMed:16035109] [WorldCat] [DOI]
  17. ↑ Nakatomi, H., Kuriu, T., Okabe, S., Yamamoto, S., Hatano, O., Kawahara, N., ..., & Nakafuku, M. (2002).
    Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell, 110(4), 429-41. [PubMed:12202033] [WorldCat] [DOI]
  18. ↑ Shin, D.H., Lee, K.S., Lee, E., Chang, Y.P., Kim, J.W., Choi, Y.S., ..., & Cho, S.S. (2003).
    Pax-7 immunoreactivity in the post-natal chicken central nervous system. Anatomia, histologia, embryologia, 32(6), 378-83. [PubMed:14651488] [WorldCat]
  19. ↑ Thomas, M.G., Barker, R.A., Beazley, L.D., & Ziman, M.R. (2007).
    Pax7 expression in the adult rat superior colliculus following optic nerve injury. Neuroreport, 18(2), 105-9. [PubMed:17301672] [WorldCat] [DOI]
  20. ↑ Thompson, J.A., Lovicu, F.J., & Ziman, M. (2007).
    Pax7 and superior collicular polarity: insights from Pax6 (Sey) mutant mice. Experimental brain research, 178(3), 316-25. [PubMed:17091300] [WorldCat] [DOI]
  21. ↑ Lumsden, A., & Krumlauf, R. (1996).
    Patterning the vertebrate neuraxis. Science (New York, N.Y.), 274(5290), 1109-15. [PubMed:8895453] [WorldCat] [DOI]
  22. ↑ Redies, C., & Puelles, L. (2001).
    Modularity in vertebrate brain development and evolution. BioEssays : news and reviews in molecular, cellular and developmental biology, 23(12), 1100-11. [PubMed:11746229] [WorldCat] [DOI]
  23. ↑ Crossley, P.H., Martinez, S., & Martin, G.R. (1996).
    Midbrain development induced by FGF8 in the chick embryo. Nature, 380(6569), 66-8. [PubMed:8598907] [WorldCat] [DOI]
  24. ↑ Ericson, J., Morton, S., Kawakami, A., Roelink, H., & Jessell, T.M. (1996).
    Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell, 87(4), 661-73. [PubMed:8929535] [WorldCat] [DOI]
  25. ↑ Fedtsova, N., Quina, L.A., Wang, S., & Turner, E.E. (2008).
    Regulation of the development of tectal neurons and their projections by transcription factors Brn3a and Pax7. Developmental biology, 316(1), 6-20. [PubMed:18280463] [PMC] [WorldCat] [DOI]
  26. ↑ Fogel, J.L., Chiang, C., Huang, X., & Agarwala, S. (2008).
    Ventral specification and perturbed boundary formation in the mouse midbrain in the absence of Hedgehog signaling. Developmental dynamics : an official publication of the American Association of Anatomists, 237(5), 1359-72. [PubMed:18429041] [PMC] [WorldCat] [DOI]
  27. ↑ Joyner, A.L. (1996).
    Engrailed, Wnt and Pax genes regulate midbrain--hindbrain development. Trends in genetics : TIG, 12(1), 15-20. [PubMed:8741855] [WorldCat] [DOI]
  28. ↑ Liem, K.F., Tremml, G., Roelink, H., & Jessell, T.M. (1995).
    Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell, 82(6), 969-79. [PubMed:7553857] [WorldCat] [DOI]
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    The role of bone morphogenetic proteins in vertebral development. Development (Cambridge, England), 122(11), 3607-16. [PubMed:8951076] [WorldCat]
  30. ↑ Schwarz, M., Alvarez-Bolado, G., Dressler, G., Urbánek, P., Busslinger, M., & Gruss, P. (1999).
    Pax2/5 and Pax6 subdivide the early neural tube into three domains. Mechanisms of development, 82(1-2), 29-39. [PubMed:10354469] [WorldCat] [DOI]
  31. ↑ Soukkarieh, C., Agius, E., Soula, C., & Cochard, P. (2007).
    Pax2 regulates neuronal-glial cell fate choice in the embryonic optic nerve. Developmental biology, 303(2), 800-13. [PubMed:17173889] [WorldCat] [DOI]
  32. ↑ Takahashi, M., & Osumi, N. (2002).
    Pax6 regulates specification of ventral neurone subtypes in the hindbrain by establishing progenitor domains. Development (Cambridge, England), 129(6), 1327-38. [PubMed:11880342] [WorldCat]
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