The mechanism regulating the development of thymic epithelial cells

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08884
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: The University of Tokushima
• Principal Investigator: OHIGASHI Izumi 徳島大学, 先端酵素学研究所(プロテオ), 准教授 (00596588)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 胸腺 / 胸腺上皮細胞 / プロテオーム / プロテアソーム / 精巣 / 生殖機能

Outline of Final Research Achievements

We did comprehensive expression analysis of cTECs and mTECs and isolated transcriptional regulators that showed significant expression difference between cTECs and mTECs. We found that mice deficient in a homeobox transcription factor highly detected in cTECs showed thymus hypoplasia and reduced expression of cTEC-genes. We also focused on PITHD1 highly detected in cTECs. PITHD1 has a putative proteasome binding domain, but is functionally unknown gene. We found that PITHD1 bind with proteasomes in the testis but not in the thymus. PITHD1-KO mice showed severe male infertility accompanied with morphological and motile abnormalities of sperm. PITHD1 deficiency reduced proteasome activity in the testis and altered the amount of proteins important for fertilization capability. However, the PITHD1-KO mice showed no detectable defects in the thymus. Collectively, our results identify PITHD1 as a proteasome-interacting protein that plays a nonredundant role in the male reproductive system.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

本研究では、これまで技術的に困難であったcTECとmTECの網羅的なプロテオーム解析を行い、トランスクリプトームプロファイルと統合することで、これらの細胞における網羅的な発現プロファイルを明らかにした。これは、T 細胞の抗原認識特異性レパトアの形成を担う胸腺微小環境の構築機構の基盤理解に向けての有用な研究リソースになると考えられる。また、cTECとmTECの発現プロファイルから注目したPITHD1は、予想外なことに、雄性生殖能に重要なプロテアソーム会合分子であることを明らかにした。この発見は、男性不妊の原因となる分子機構の解明、および、治療法開発につながると考えられる。