Selected mRNA translation and congenital pure red-cell aplasia: Studying the molecular pathogenesis of the anemia using zebrafish as a model system

• Project/Area Number: 24591556
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: University of Miyazaki
• Principal Investigator: UECHI Tamayo 宮崎大学, フロンティア科学実験総合センター, 研究員 (10381104)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: リボソームタンパク質遺伝子 / 翻訳異常 / ゼブラフィッシュ / ダイアモンド・ブラックファン貧血 / リボソームタンパク質 / 骨髄不全 / リボソーム病 / ダイヤモンド・ブラックファン貧血

Outline of Final Research Achievements

More than ten ribosomal protein (RP) genes have been identified in 60% of the Diamond-Blackfan anemia (DBA) patients. We speculated that translation efficiency of specific mRNAs required for erythropoiesis was altered due to RP gene mutations. To evaluate the impact of RP deficiency on translation, we carried out microarray analysis of total mRNAs and RNA-seq analysis of polysomal mRNAs using zebrafish model of DBA. Comparing the data from both analyses enabled us to calculate the net translation efficiency. We found that the expression of 75 genes was repressed by more than 50%. Eight genes among the most repressed 50 genes were found to be involved in hematopoiesis. In-vitro synthesized mRNA of one of these genes partially rescued the anemia phenotype in the DBA model. These data should provide an important clue to the pathogenesis of DBA.

Research Products

• [Journal Article] scaRNAs regulate splicing and vertebrate heart development. (2015)
  • Author(s): Patil, P., Kibiryeva, N., Uechi, T., Marshall, J., Artman, M., O'Brien, J.E., Kenmochi, N. and Bittel, D.C.
  • Journal Title: Biochimica et Biophysica Acta-Molecular Basis of Disease Volume: 未定 Issue: 8 Pages: 1619-1629
  • DOI: 10.1016/j.bbadis.2015.04.016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Incomplete splicing of neutrophil-specific genes affects neutrophil development in a zebrafish model of poikiloderma with neutropenia (2015)
  • Author(s): Patil P, Uechi T, Kenmochi N
  • Journal Title: RNA Biology Volume: 12 Issue: 4 Pages: 426-434
  • DOI: 10.1080/15476286.2015.1017240
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Loss of function mutations in RPL27 and RPS27 identified by whole-exome sequencing in Diamond-Blackfan anaemia. (2015)
  • Author(s): Wang R, Yoshida K, Toki T, Sawada T, Uechi T, Okuno Y, Sato-Otsubo A, Kudo K, Kamimaki I, Kanezaki R, Shiraishi Y, Chiba K, Tanaka H, Terui K, Sato T, Iribe Y, Ohga S, Kuramitsu M, Hamaguchi I, Ohara A, Hara J, et al.
  • Journal Title: British Journal of Haematology Volume: 168 Issue: 6 Pages: 854-864
  • DOI: 10.1111/bjh.13229
  • Peer Reviewed / Open Access
• [Journal Article] Ribosomal protein deficiency causes Tp53-independent erythropoiesis failure in zebrafish (2014)
  • Author(s): Yadav V.G., Chakraborty A., Uechi T., and Kenmochi N.
  • Journal Title: Int. J. Biochem. Cell Biol. Volume: 49 Pages: 1-7
  • DOI: 10.1016/j.biocel.2014.01.006
  • Peer Reviewed
• [Journal Article] 第1章リボソーム：リボソームタンパク質と翻訳制御 (2012)
  • Author(s): 上地珠代、剣持直哉
  • Journal Title: 生体の科学：細胞の分子構造と機能－核以外の細胞小器官 Volume: 63 Pages: 362-363
• [Presentation] Decreased translation efficiency of mRNAs required for hematopoiesis in a zebrafish model of Diamond-Blackfan anemia (2016)
  • Author(s): Tamayo Uechi, Yukari Nakajima, Maki Yoshihama, Tsutomu Toki, Yutaka Suzuki, Sumio Sugano, Etsuro Ito and Naoya Kenmochi
  • Organizer: The 14th Diamond Blackfan Anemia International Consensus Conference
  • Place of Presentation: アトランタ（米国）
  • Year and Date: 2016-03-05
  • Int'l Joint Research
• [Presentation] ゼブラフィッシュを用いたリボソーム病発症メカニズムの解明 (2015)
  • Author(s): 上地珠代, 中島由香里, 吉浜麻生, 鈴木穣, 菅野純夫, 剣持直哉
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] リボソーム病モデルを用いた発症機序の解明と化合物スクリーニング (2015)
  • Author(s): 上地珠代, 吉浜麻生, 中島由香里, 上米良美香, 剣持直哉
  • Organizer: 第1回ゼブラフィッシュ創薬研究会
  • Place of Presentation: 津
  • Year and Date: 2015-11-06
• [Presentation] Selected mRNA translation and ribosomopathies: studying the molecular pathogenesis of congenital anemia using zebrafish as a model system (2015)
  • Author(s): Tamayo Uechi, Yukari Nakajima, Maki Yoshihama, Yutaka Suzuki, Sumio Sugano, and Naoya Kenmochi
  • Organizer: International Conference on Ribosome Synthesis
  • Place of Presentation: ブリュッセル（ベルギー）
  • Year and Date: 2015-08-19
  • Int'l Joint Research
• [Presentation] 選択的な翻訳制御と疾患：ゼブラフィッシュを用いたリボソーム病発症機構の解明 (2014)
  • Author(s): 上地 珠代, 中島 由香里, Gnaneshwar Yadav, 吉浜 麻生, 鈴木 穣, 菅野 純夫, 剣持 直哉
  • Organizer: 第37回分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Defects in ribosomal proteins cause erythroid failure in a zebrafish model of Diamond-Blackfan anemia (2014)
  • Author(s): Tamayo Uechi, Yukari Nakajima, Gnaneshwar Yadav, Maki Yoshihama, Yutaka Suzuki, Sumio Sugano, and Naoya Kenmochi
  • Organizer: 第２０回小型魚類研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-09-20 – 2014-09-21
• [Presentation] Studying the molecular pathogenesis of Diamond-Blackfan anemia using zebrafish as a model system (2014)
  • Author(s): Tamayo Uechi, Yukari Nakajima, Gnaneshwar Yadav, Maki Yoshihama, Yutaka Suzuki, Sumio Sugano, and Naoya Kenmochi
  • Organizer: The 14th Conference on Translational Control
  • Place of Presentation: コールドスプリングハーバー（米国）
  • Year and Date: 2014-09-02 – 2014-09-06
• [Presentation] Ribosome dysfunction and erythroid failure: Analyzing the zebrafish model of Diamond-Blackfan anemia (2014)
  • Author(s): Tamayo Uechi, Yukari Nakajima, Gnaneshwar Yadav, Yutaka Suzuki, Sumio Sugano, and Naoya Kenmochi
  • Organizer: The 19th Annual Meeting of the RNA Society
  • Place of Presentation: ケベック（カナダ）
  • Year and Date: 2014-06-03 – 2014-06-08
• [Presentation] Analyzing the zebrafish model of Diamond-Blackfan anemia (2014)
  • Author(s): Tamayo Uechi, Yukari Nakajima, Gnaneshwar V. Yadav, Yutaka Suzuki, Sumio Sugano, Naoya Kenmochi
  • Organizer: 13th Diamond Blackfan Anemia International Consensus Conference
  • Place of Presentation: アトランタ（米国）
• [Presentation] 翻訳の異常とリボソーム病：ゼブラフィッシュを用いた発症メカニズムの解明 (2013)
  • Author(s): 上地珠代，中島 由香里，ヤダフ グナネシュワ，パティル プルカッシュ，鈴木 穣，菅野 純夫，剣持 直哉
  • Organizer: 第36回 日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド
• [Presentation] Molecular pathogenesis of ribosomopaties in zebrafish model for Diamond-Blackfan anemia (2013)
  • Author(s): Tamayo Uechi, Yukari Nakajima, Hiroko Sonoda, Masahiro Ikeda, Yutaka Suzuki, Sumio Sugano, Naoya Kenmochi
  • Organizer: The 18th annual meeting of the RNA Society
  • Place of Presentation: ダボス（スイス）
• [Presentation] ゼブラフィッシュ貧血モデルを用いたリボソーム病発症機構の解析 (2012)
  • Author(s): 上地珠代
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] Defective erythropoiesis due to ribosome dysfunction in zebrafish (2012)
  • Author(s): Tamayo Uechi
  • Organizer: International Conference on Ribosome Synthesis
  • Place of Presentation: Banff, Canada
• [Presentation] リボソームの翻訳異常と赤血球形成不全：ゼブラフィッシュの貧血モデルを用いた解析 (2012)
  • Author(s): 上地 珠代
  • Organizer: 第14回日本RNA学会年会
  • Place of Presentation: 仙台
• [Book] 第2章 動物実験の対象：ゼブラフィッシュ, 第3章 動物の飼育管理・基本的手技：魚類（ゼブラフィッシュ）, 第4章 動物実験手法：ゼブラフィッシュを用いた疾患モデルの作製・解析. 大・中・小動物実験プロトコル (2016)
  • Author(s): 上地珠代, 剣持直哉
  • Total Pages: 146
  • Publisher: 宮日文化情報センター