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Genetic Deficiency of Mtdh Gene in Mice Causes Male Infertility via Impaired Spermatogenesis and Alterations in the Expression of Small Non-coding RNAs
Journal article   Open access   Peer reviewed

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

Xiangbing Meng, Shujie Yang, Yuping Zhang, Xinjun Wang, Renee X Goodfellow, Yichen Jia, Kristina W Thiel, Henry D Reyes, Baoli Yang and Kimberly K Leslie
The Journal of biological chemistry, Vol.290(19), pp.11853-11864
05/08/2015
DOI: 10.1074/jbc.M114.627653
PMCID: PMC4424326
PMID: 25787082
url
https://doi.org/10.1074/jbc.M114.627653View
Published (Version of record) Open Access

Abstract

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.
 DNA Repair Testis - metabolism Spermatocytes - metabolism Spermatogenesis - genetics Exons Membrane Proteins - genetics Gene Expression Regulation Genotype In Situ Hybridization, Fluorescence Male MicroRNAs - metabolism Mice, Knockout Homozygote Animals Infertility, Male - genetics Membrane Proteins - physiology Gene Deletion Spermatozoa - physiology Mice DNA Damage RNA, Small Untranslated - metabolism

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