Identifying epigenetic mechanisms for testicular development and developing innovative technology for regenerative medicine

• Project/Area Number: 15K09615
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KASHIMADA Kenichi 東京医科歯科大学, 医学部附属病院, 講師 (80451938)
• Co-Investigator(Kenkyū-buntansha): 森尾 友宏 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30239628)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 性分化 / エピジェネティックス / 精巣 / CRSPR/Cas9 / シトルリン化 / 発生 / 再生医療 / セルトリ細胞

Outline of Final Research Achievements

In this study, we aimed to clarify epigenetic mechanisms in development of the testicular supporting cells, Sertoli cells.
Peptidylarginine deiminases (PADs) are a family of enzymes that change the charge of target proteins through citrullination. We identified Padi2 which encodes PAD2 was exclusively expressed in Sertoli cells of fetal developing testes. Our data suggested that Padi2 was a novel gene in fetal testis development which was specifically expressed in Sertoli cells through the regulation of SOX9 and FOXL2 and supported regulation by SOX9 for target genes. The phenotype of Padi2(-/-)XY indicates that a redundant factor compensates for the role of PAD2 in testicular development.

Research Products

• [Journal Article] TALEN-Mediated Gene Disruption on Y Chromosome Reveals Critical Role of EIF2S3Y in Mouse Spermatogenesis. (2015)
  • Author(s): Matsubara Y, Kato T, Kashimada K, Tanaka H, Zhi Z, Ichinose S, Mizutani S, Morio T, Chiba T, Ito Y, Saga Y, Takada S, Asahara H.
  • Journal Title: Stem Cells Dev Volume: 15 Pages: 1164-70
  • Peer Reviewed
• [Journal Article] A 45,X/46,XY DSD (Disorder of Sexual Development) case with an extremely uneven distribution of 46,XY cells between lymphocytes and gonads (2015)
  • Author(s): Nomura R, Miyai K, Okada M, Kajiwara M, Ono M, Ogata T, Onishi I, Sato M, Sekine M, Akashi T, Mizutani S, Kashimada K
  • Journal Title: Clinical Pediatric Endocrinology Volume: 24 Issue: 1 Pages: 11-14
  • DOI: 10.1297/cpe.24.11
  • NAID: 130004853607
  • ISSN: 0918-5739, 1347-7358
  • Peer Reviewed
• [Presentation] SOX9により促進的発現制御を受けるPAD2の精巣分化における役割 (2018)
  • Author(s): 鹿島田 健一
  • Organizer: 第91回 日本内分泌学会
• [Presentation] SOX9 and FOXL2 antagonistically regulate peptidyl arginine deiminase 2 (Padi2) expression during testicular development (2018)
  • Author(s): Kenichi Kashimada
  • Organizer: 8th International Symposium on Vertebrate Sex Determination
  • Int'l Joint Research
• [Presentation] SOX9 and FOXL2 antagonistically regulate peptidyl arginine deiminase 2 (Padi2) expression during testicular development (2018)
  • Author(s): Atsumi Hosokawa-Tsuji
  • Organizer: ENDO 2018 第100回米国内分泌学会議
  • Int'l Joint Research
• [Presentation] 性分化における分子機構の新たな展開に向けて (2016)
  • Author(s): 鹿島田 健一
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: 神奈川県 横浜市 パシフィコ横浜 日本
  • Invited
• [Presentation] TALEN-Mediated Gene Disruption on Y Chromosome Reveals Critical Role of EIF2S3Y in Mouse Spermatogenesis. (2015)
  • Author(s): Kenichi Kashimada, Yohei Matsubara, Tomoko Kato, Takashi Nakasuji, Hiromitsu Tanaka, Zhou Zhi, Shizuko Ichinose, Tomoki Chiba, Yoshiaki Ito, Yumiko Saga, Tomohiro Morio, Shuji Takada, Hiroshi Asahara.
  • Organizer: Germinal Stem Cell Biology, Gordon Research Conference
  • Place of Presentation: The Chinese University of Hong Kong,Hong Kong, China
  • Year and Date: 2015-05-31
  • Int'l Joint Research
• [Remarks] 東京医科歯科大学小児科学教室ホームページ 性分化の機構
  • URL: http://www.tmd.ac.jp/med/ped/medical/research/life_theme.html#04