title: Genetic Deficiency of Mtdh Gene in Mice Causes Male Infertility via Impaired Spermatogenesis and Alterations in the Expression of Small Non-coding RNAs.
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.
authors: From the Department of Obstetrics and Gynecology and Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa 52242 xiangbing-meng@uiowa.edu.
authors: Xiangbing
authors: X
authors: Meng
authors: From the Department of Obstetrics and Gynecology and Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa 52242.
authors: Shujie
authors: S
authors: Yang
authors: From the Department of Obstetrics and Gynecology and.
authors: Yuping
authors: Y
authors: Zhang
authors: From the Department of Obstetrics and Gynecology and.
authors: Xinjun
authors: X
authors: Wang
authors: From the Department of Obstetrics and Gynecology and.
authors: Renee X
authors: RX
authors: Goodfellow
authors: From the Department of Obstetrics and Gynecology and.
authors: Yichen
authors: Y
authors: Jia
authors: From the Department of Obstetrics and Gynecology and.
authors: Kristina W
authors: KW
authors: Thiel
authors: From the Department of Obstetrics and Gynecology and.
authors: Henry D
authors: HD
authors: Reyes
authors: From the Department of Obstetrics and Gynecology and.
authors: Baoli
authors: B
authors: Yang
authors: From the Department of Obstetrics and Gynecology and Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa 52242.
authors: Kimberly K
authors: KK
authors: Leslie
mesh_terms: D000818:Animals; D004249:DNA Damage; D004260:DNA Repair; D005091:Exons; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005838:Genotype; D006720:Homozygote; D017404:In Situ Hybridization, Fluorescence; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D058727:RNA, Small Untranslated / Q000378:metabolism*; D016601:RNA-Binding Proteins; D013090:Spermatocytes / Q000378:metabolism; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000502:physiology; D013737:Testis / Q000378:metabolism
chemical_list: C561642:MIRN19 microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; C522604:Mirn16 microRNA, mouse; C483038:Mtdh protein, mouse; D058727:RNA, Small Untranslated; D016601:RNA-Binding Proteins
keywords: AEG-1; DNA Damage; Development; MTDH; Male Infertility; Meiosis; MicroRNA (miRNA); Mili; Pachytene; Rad18; Reproduction; Spermatogenesis; piRNA