Functional investigation of Cables2, a novel transcription cofactor regulating Nanog expression through Smad2 activation, during germ cell development

• Project/Area Number: 19K16020
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 42040:Laboratory animal science-related
• Research Institution: University of Tsukuba
• Principal Investigator: DINH T.H.TRA 筑波大学, 医学医療系, 助教 (30816476)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: Cables2 / embryogenesis / mouse / germ cell / primordial germ cell / Smad2 / Nanog

Outline of Research at the Start

Cables2 was a novel transcription cofactor of Nodal/Smad2 signaling pathways in regulating Nanog expression in gastrulation. This study will investigate the mechanism of how Cables2 regulates Nanog expression and Smad2 transcriptional activation in primordial germ cells and germ cells.

Outline of Final Research Achievements

CDK5 and Abl enzyme substrate 2 (Cables2), a member of the Cables family, is ubiquitously expressed in mouse embryonic and reproductive organs at the RNA level, suggesting the existence and contribution of Cables2 in embryonic and germ cell development. However, in vivo function of Cables2 remains unclear. Therefore, in this study, we aimed to explore the role of Cables2 using mouse models.
Using genetically modified mouse models, we found that the entire Cables2 locus is essential for early mouse embryogenesis. Transcriptome profiling comparison revealed that Cables2 indeed involved in male gonad development and fundamental signaling pathways such as Wnt and P53. In addition, we successfully generated a Cables2 knock-in reporter model in which Cables2 is demonstrated to be expressed in mouse testis and ovary, the main reproductive organs. Generally, this study highlights the sophisticated role of Cables2 in mouse development.

Academic Significance and Societal Importance of the Research Achievements

This study firstly report about the essential of Cables2 locus in mouse development. Cables2 is clarified to be expressed in various mouse tissues including testis, ovary, brain, etc. In addition, this study focus attention on the need to validate target knock-out genes in lethal phenotypes.

Research Products

• [Journal Article] Characterization of a bicistronic knock-in reporter mouse model for investigating the role of CABLES2 <i>in vivo</i> (2021)
  • Author(s): Hasan Ammar Shaker Hamed、Dinh Tra Thi Huong、Le Hoai Thu、Mizuno-Iijima Saori、Daitoku Yoko、Ishida Miyuki、Tanimoto Yoko、Kato Kanako、Yoshiki Atsushi、Murata Kazuya、Mizuno Seiya、Sugiyama Fumihiro
  • Journal Title: Experimental Animals Volume: 70 Issue: 1 Pages: 22-30
  • DOI: 10.1538/expanim.20-0063
  • NAID: 130007981753
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Disruption of entire Cables2 locus leads to embryonic lethality by diminished Rps21 gene expression and enhanced p53 pathway (2021)
  • Author(s): Dinh Tra Thi Huong、Iseki Hiroyoshi、Mizuno Seiya、Iijima-Mizuno Saori、Tanimoto Yoko、..., Murata Kazuya、Muratani Masafumi、Ema Masatsugu、Kim Jun-Dal、Ishida Junji、Fukamizu Akiyoshi、Kato Mitsuyasu、Takahashi Satoru、Yagami Ken-ichi、Wilson Valerie、Arkell Ruth M、Sugiyama Fumihiro
  • Journal Title: eLife Volume: 10
  • DOI: 10.7554/elife.50346
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Disruption of entire Cables2 locus leads to embryonic lethality by diminished Rps21 gene expression and enhanced p53 pathway (2021)
  • Author(s): Tra Thi Huong Dinh, Hiroyoshi Iseki, Seiya Mizuno, Satoru Takahashi, and Fumihiro Sugiyama
  • Organizer: The 94th Annual Meeting of the Japanese Biochemical Society (JBS), 2T14a-06 (P-610)
• [Presentation] The essential of entire Cables2 locus for early embryonic development in mice. (2021)
  • Author(s): Tra Thi Huong Dinh, Hiroyoshi Iseki, Seiya Mizuno, Masatsugu Ema, Akiyoshi Fukamizu, Satoru Takahashi, Ken-ichi Yagami and Fumihiro Sugiyama
  • Organizer: The 44th Annual Meeting of the Molecular Biology Society of Japan (MBSJ), 3LBA-051
• [Presentation] Cables2 regulates mouse gastrulation by stimulating Wnt/beta-catenin signalling pathway (2019)
  • Author(s): Tra Thi Huong Dinh, Hiroyoshi Iseki, Seiya Mizuno, Saori Iijima-Mizuno, Yoko Tanimoto, Yoko Daitoku, Kanako Kato, Masatsugu Ema, Akiyoshi Fukamizu, Mitsuyasu Kato, Satoru Takahashi, Ken-ichi Yagami, Fumihiro Sugiyama
  • Organizer: The 2019 International Symposium of Korean Association for Laboratory Animal Sciences (KALAS)
  • Int'l Joint Research / Invited