Retinoid signals to control spermatogonial stem cells differentiation

• Project/Area Number: 19K16027
• 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: Nagoya City University
• Principal Investigator: Shawki Hossam 名古屋市立大学, 医薬学総合研究院(医学), 助教 (70829738)
• 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 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 精子形成 / 腎足細胞 / 大Maf群転写因子 / タンパク尿 / Large Maf / Transcription factor / Spermatogenesis / Testis / Mafb / Transcriptions Factor / spermatogenesis / transcription factor / spermatogonial stem cell

Outline of Research at the Start

We will examine whether MAFB transcription factor is the direct target of retinoic acid using a conditional deletion mouse of MAFB in testes. We also found that c-MAF gene is also expressed in Sertoli cells. In the second year, we are planning to generate sertoli-cell specific MAFB/c-MAF double cKO to clarify the retinoic acid signaling pathway in spermatogenesis initiation and rescue the phenomena of azoospermia.

Outline of Final Research Achievements

Vitamin A is synthesized into retinoic acid (RA), an important regulator of various cell differentiations, including spermatogonia and podocytes. In this study, we identified MafB and cMaf as new targets for RA. RA has confirmed that it directly regulates MafB and c-Maf and induces their expression, especially in cultured Sertoli cells and podocytes. On the other hand, urinary protein levels increased in MafB and c-Maf double-deficient mice, and glomerular RNA-seq analysis showed that slit diaphragm-related proteins (Magi2) and podocyte-specific transcription factors (Tcf21) were down. Clarified the regulation.

Academic Significance and Societal Importance of the Research Achievements

レチノイン酸シグナルは、全身で多彩な役割を果たしており、その標的遺伝子を含むカスケードの全貌を明らかにすることは、脳神経疾患や各種悪性腫瘍の予防や治療に大きな貢献をすると期待される。本研究では、精子形成および腎臓足細胞におけるシグナルの下流遺伝子と生理的役割を同定しており、この分野における更なる発展が期待できる。

Research Products

• [Int'l Joint Research] Baylor College of Medicine(米国)
• [Journal Article] CRISPR/Cas9-based genome editing in mice uncovers 13 testis- or epididymis-enriched genes individually dispensable for male reproduction (2020)
  • Author(s): Sun Jiang、Lu Yonggang、Nozawa Kaori、Xu Zoulan、Morohoshi Akane、Castaneda Julio M、Noda Taichi、Miyata Haruhiko、Abbasi Ferheen、Shawki Hossam H、Takahashi Satoru、Devlin Darius J、Yu Zhifeng、Matzuk Ryan M、Garcia Thomas X、Matzuk Martin M、Ikawa Masahito
  • Journal Title: Biology of Reproduction Volume: N/A Issue: 2 Pages: 183-194
  • DOI: 10.1093/biolre/ioaa083
  • NAID: 120007190927
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EFCAB2 is a novel calcium-binding protein in mouse testis and sperm. (2019)
  • Author(s): Shawki HH*, Ishikawa-Yamauchi Y*, Kawashima A, Katoh Y, Matsuda M, Al-Soudy AS, Minisy FM, Kuno A, Gulibaikelamu X, Hirokawa T, Takahashi S, Oishi H. (* equal first)
  • Journal Title: PLoS One Volume: 14(4) Issue: 4 Pages: 0214687-0214687
  • DOI: 10.1371/journal.pone.0214687
  • Peer Reviewed / Open Access / Int'l Joint Research