Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 19, Pages 11853-11864Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.627653
Keywords
Development; DNA Damage; Meiosis; MicroRNA (miRNA); Reproduction; Spermatogenesis; MTDH; Male Infertility; Pachytene; piRNA; AEG-1; Mili; Rad18
Categories
Funding
- National Institutes of Health [R01CA184101, R01CA99908]
- Department of Obstetrics and Gynecology Research Development Fund
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Background: MTDH is associated with poor prognosis in cancer, yet its biologic function is unclear. Results:Mtdh-null male mice are infertile, with a lack of mature sperm in testes and altered expression of small non-coding RNAs. Conclusion:Mtdh deficiency results in male infertility due to impaired spermatogenesis. Significance: The oncogene MTDH plays an indispensable role in male fertility. 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 -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.
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