• PMID: 25787082
• Gene Name: MTDH
• Condition: Impaired spermatogenesis, Male infertility
• Association: Associated
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Impaired spermatogenesis, Male infertility

Genetic Deficiency of Mtdh Gene in Mice Causes Male Infertility via Impaired Spermatogenesis and Alterations in the Expression of Small Non-coding RNAs

Meng X, Yang S, Zhang Y, Wang X, Goodfellow RX, Jia Y, Thiel KW, Reyes HD, Yang B, Leslie KK.

Increased expression of metadherin (MTDH, also known as AEG-1 and 3D3/LYRIC) has been associated with drug resistance, metastasis, and angiogenesis in a variety of cancers. However, the specific mechanisms through which MTDH is involved in these processes remain unclear. To uncover these mechanisms, we generated Mtdh knock-out mice via a targeted disruption of exon 3. Homozygous Mtdh knock-out mice are viable, but males are infertile. The homozygous male mice present with massive loss of spermatozoa as a consequence of meiotic failure. Accumulation of γ-H2AX in spermatocytes of homozygous Mtdh knock-out mice confirms an increase in unrepaired DNA breaks. We also examined expression of the DNA repair protein Rad18, which is regulated by MTDH at the post-transcriptional level. In testes from Mtdh exon 3-deficient mice, Rad18 foci were increased in the lumina of the seminiferous tubules. The Piwi-interacting RNA (piRNA)-interacting protein Mili was expressed at high levels in testes from Mtdh knock-out mice. Accordingly, genome-wide small RNA deep sequencing demonstrated altered expression of piRNAs in the testes of Mtdh knock-out mice as compared with wild type mice. In addition, we observed significantly reduced expression of microRNAs (miRNAs) including miR-16 and miR-19b, which are known to be significantly reduced in the semen of infertile men. In sum, our observations indicate a crucial role for MTDH in male fertility and the DNA repair mechanisms required for normal spermatogenesis. CI - © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Meng, Xiangbing AU - Meng X AD - From the Department of Obstetrics and Gynecology and Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa 52242 xiangbing-meng@uiowa.edu. FAU - Yang, Shujie AU - Yang S AD - From the Department of Obstetrics and Gynecology and Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa 52242. FAU - Zhang, Yuping AU - Zhang Y AD - From the Department of Obstetrics and Gynecology and. FAU - Wang, Xinjun AU - Wang X AD - From the Department of Obstetrics and Gynecology and. FAU - Goodfellow, Renee X AU - Goodfellow RX AD - From the Department of Obstetrics and Gynecology and. FAU - Jia, Yichen AU - Jia Y AD - From the Department of Obstetrics and Gynecology and. FAU - Thiel, Kristina W AU - Thiel KW AD - From the Department of Obstetrics and Gynecology and. FAU - Reyes, Henry D AU - Reyes HD AD - From the Department of Obstetrics and Gynecology and. FAU - Yang, Baoli AU - Yang B AD - From the Department of Obstetrics and Gynecology and.