Mutation of <i>Eif4g3</i>, encoding a eukaryotic translation initiation factor, causes male infertility and meiotic arrest of mouse spermatocytes

Sun, Fengyun; Palmer, Kristina; Handel, Mary Ann

doi:10.1242/dev.043125

Cited by 66 publications

(70 citation statements)

References 58 publications

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“…In addition, at least Mtap2, Eif4g3, Usp2, Mtap7, Ace, and Tex14 are known to play a role in male fertility (29)(30)(31)(32)(33)(34), and overexpression of Spata17 and Rpgr leads to male infertility (35,36). Therefore, the infertility in the Mrg15 cKO mice could be secondary to alterations in the levels of these proteins.…”

Section: Spermatogenesis In Mrg15mentioning

confidence: 99%

MRG15 is required for pre-mRNA splicing and spermatogenesis

Iwamori

Tominaga

Sato

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Splicing can be epigenetically regulated and involved in cellular differentiation in somatic cells, but the interplay of epigenetic factors and the splicing machinery during spermatogenesis remains unclear. To study these interactions in vivo, we generated a germline deletion of MORF-related gene on chromosome 15 (MRG15), a multifunctional chromatin organizer that binds to methylated histone H3 lysine 36 (H3K36) in introns of transcriptionally active genes and has been implicated in regulation of histone acetylation, homology-directed DNA repair, and alternative splicing in somatic cells. Conditional KO (cKO) males lacking MRG15 in the germline are sterile secondary to spermatogenic arrest at the round spermatid stage. There were no significant alterations in meiotic division and histone acetylation. Specific mRNA sequences disappeared from 66 germ cell-expressed genes in the absence of MRG15, and specific intronic sequences were retained in mRNAs of 4 genes in the MRG15 cKO testes. In particular, introns were retained in mRNAs encoding the transition proteins that replace histones during sperm chromatin condensation. In round spermatids, MRG15 colocalizes with splicing factors PTBP1 and PTBP2 at H3K36me3 sites between the exons and single intron of transition nuclear protein 2 (Tnp2). Thus, our results reveal that MRG15 is essential for premRNA splicing during spermatogenesis and that epigenetic regulation of pre-mRNA splicing by histone modification could be useful to understand not only spermatogenesis but also, epigenetic disorders underlying male infertile patients.infertility | fertility defects | splicing defects | epigenetics | spermiogenesis S permatogenesis is a complex process involving several biological events and dramatic changes of chromatin structure. Male germ cells undergo stem cell self-renewal, mitotic divisions in spermatogonial proliferation, genomic rearrangement by meiotic homologous recombination at the spermatocyte stage, and morphological changes of round spermatids into elongated spermatids to form mature spermatozoa (1-3). During spermiogenesis, nucleosomal histone proteins are replaced with transition nuclear proteins (TNPs) and subsequently, protamines, the major nucleosomal proteins in spermatozoa. Moreover, epigenetic modifications, such as histone methylation, dramatically change throughout spermatogenesis (3, 4).Pre-mRNA splicing generates protein diversity and is involved in the regulation of cellular differentiation (5, 6). Recent advances have shown that histone modifications regulate alternative splicing through recruitment of splicing regulators via chromatin binding proteins, such as MORF-related gene on chromosome 15 (MRG15) (7). Histone H3 lysine 36 (H3K36) is methylated proximal to tissuespecific splicing regions (8-12). MRG15 specifically recognizes the methylated H3K36 and recruits polypyrimidine tract binding protein (PTB) at intronic splicing silencer elements near an exon to suppress exon insertions into mRNA (7). MRG15 is also a component of histone acetyltransfe...

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Section: Spermatogenesis In Mrg15mentioning

confidence: 99%

MRG15 is required for pre-mRNA splicing and spermatogenesis

Iwamori

Tominaga

Sato

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In mouse spermatocytes, another eIF4G family member, eIF4g3, is necessary for the meiotic cell cycle [39]. Spermatocytes of eIF4g3 mutants progress through prophase I, because they go through recombination as well as synaptonemal complex assembly and disassembly, but they do not undergo the meiotic divisions.…”

Section: Developmental Control Of the Cell Cycle Via Translational Rementioning

confidence: 99%

Translational regulation of the cell cycle: when, where, how and why?

Kronja

Orr‐Weaver

2011

Phil. Trans. R. Soc. B

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Translational regulation contributes to the control of archetypal and specialized cell cycles, such as the meiotic and early embryonic cycles. Late meiosis and early embryogenesis unfold in the absence of transcription, so they particularly rely on translational repression and activation of stored maternal mRNAs. Here, we present examples of cell cycle regulators that are translationally controlled during different cell cycle and developmental transitions in model organisms ranging from yeast to mouse. Our focus also is on the RNA-binding proteins that affect cell cycle progression by recognizing special features in untranslated regions of mRNAs. Recent research highlights the significance of the cytoplasmic polyadenylation element-binding protein (CPEB). CPEB determines polyadenylation status, and consequently translational efficiency, of its target mRNAs in both transcriptionally active somatic cells as well as in transcriptionally silent mature Xenopus oocytes and early embryos. We discuss the role of CPEB in mediating the translational timing and in some cases spindle-localized translation of critical regulators of Xenopus oogenesis and early embryogenesis. We conclude by outlining potential directions and approaches that may provide further insights into the translational control of the cell cycle.

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“…45 Such programs have revealed many critical genes for human diseases, including male infertility. [46][47][48][49] …”

Section: Mouse Models In Male Fertility Research D Jamsai and Mk O'brmentioning

confidence: 99%

Mouse models in male fertility research

Jamsai¹,

O'Bryan²

2010

Asian J Androl

114

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Limited knowledge of the genetic causes of male infertility has resulted in few treatment and targeted therapeutic options. Although the ideal approach to identify infertility causing mutations is to conduct studies in the human population, this approach has progressed slowly due to the limitations described herein. Given the complexity of male fertility, the entire process cannot be modeled in vitro. As such, animal models, in particular mouse models, provide a valuable alternative for gene identification and experimentation. Since the introduction of molecular biology and recent advances in animal model production, there has been a substantial acceleration in the identification and characterization of genes associated with many diseases, including infertility. Three major types of mouse models are commonly used in biomedical research, including knockout/knockin/gene-trapped, transgenic and chemical-induced point mutant mice. Using these mouse models, over 400 genes essential for male fertility have been revealed. It has, however, been estimated that thousands of genes are involved in the regulation of the complex process of male fertility, as many such genes remain to be characterized. The current review is by no means a comprehensive list of these mouse models, rather it contains examples of how mouse models have advanced our knowledge of post-natal germ cell development and male fertility regulation.

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Mutation of Eif4g3, encoding a eukaryotic translation initiation factor, causes male infertility and meiotic arrest of mouse spermatocytes

Cited by 66 publications

References 58 publications

MRG15 is required for pre-mRNA splicing and spermatogenesis

MRG15 is required for pre-mRNA splicing and spermatogenesis

Translational regulation of the cell cycle: when, where, how and why?

Mouse models in male fertility research

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