MicroRNAs and spermatogenesis.

In mammals, male gametes are produced inside the testis by spermatogenesis, which has three phases: mitotic proliferation of spermatogonia, meiosis of spermatocytes, and haploid differentiation of spermatids. The genome of male germ cells is actively transcribed to produce phase-specific gene expression patterns. Male germ cells have a complex transcriptome. In addition to protein-coding messenger RNAs, many noncoding RNAs, including microRNAs (miRNAs), are produced. The miRNAs are important regulators of gene expression. They function mainly post-transcriptionally to control the stability or translation of their target messenger RNAs. The miRNAs are expressed in a cell-specific manner during spermatogenesis to participate in the control of each step of male germ cell differentiation. Genetically modified mouse models have demonstrated the importance of miRNA pathways for normal spermatogenesis, and functional studies have been designed to dissect the roles of specific miRNAs in distinct cell types. Clinical studies have exploited the well-defined expression profiles of miRNAs, and human spermatozoal or seminal plasma miRNAs have been explored as potential biomarkers for male factor infertility. This review article discusses the current findings that support the central role of miRNAs in the regulation of spermatogenesis and male fertility.

[1]  S. Krawetz,et al.  The presence, role and clinical use of spermatozoal RNAs. , 2013, Human reproduction update.

[2]  Shuzhen Li,et al.  Inactivation of Dicer1 has a severe cumulative impact on the formation of mature germ cells in mouse testes. , 2012, Biochemical and biophysical research communications.

[3]  N. Kotaja,et al.  Epigenetic regulation of male germ cell differentiation. , 2013, Sub-cellular biochemistry.

[4]  I. MacRae,et al.  The RNA-induced Silencing Complex: A Versatile Gene-silencing Machine* , 2009, The Journal of Biological Chemistry.

[5]  A. Keller,et al.  Altered microRNA expression profiles of human spermatozoa in patients with different spermatogenic impairments. , 2013, Fertility and sterility.

[6]  N. Kotaja,et al.  Chromatoid body and small RNAs in male germ cells. , 2011, Reproduction.

[7]  S. Kalko,et al.  Differential RNAs in the sperm cells of asthenozoospermic patients. , 2012, Human reproduction.

[8]  Zuping He,et al.  MiRNA‐20 and mirna‐106a regulate spermatogonial stem cell renewal at the post‐transcriptional level via targeting STAT3 and Ccnd1 , 2013, Stem cells.

[9]  Selene L. Fernandez-Valverde,et al.  SOX9 Regulates MicroRNA miR-202-5p/3p Expression During Mouse Testis Differentiation1 , 2013, Biology of reproduction.

[10]  Shridar Ganesan,et al.  Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. , 2005, Genes & development.

[11]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[12]  M. Ascano,et al.  Multi-disciplinary methods to define RNA-protein interactions and regulatory networks. , 2013, Current opinion in genetics & development.

[13]  J. Rinn,et al.  Modular regulatory principles of large non-coding RNAs , 2012, Nature.

[14]  A. Milosavljevic,et al.  Analysis of MicroRNA Expression in the Prepubertal Testis , 2010, PloS one.

[15]  Wei Yan,et al.  Expression Profiling Reveals Developmentally Regulated lncRNA Repertoire in the Mouse Male Germline1 , 2013, Biology of reproduction.

[16]  W. Engel,et al.  MicroRNA signature in various cell types of mouse spermatogenesis: Evidence for stage‐specifically expressed miRNA‐221, ‐203 and ‐34b‐5p mediated spermatogenesis regulation , 2012, Biology of the cell.

[17]  P. Sassone-Corsi,et al.  Testis-specific transcription mechanisms promoting male germ-cell differentiation. , 2004, Reproduction.

[18]  N. Rajewsky,et al.  Cell-type-specific signatures of microRNAs on target mRNA expression. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[19]  James C. Carrington,et al.  Specialization and evolution of endogenous small RNA pathways , 2007, Nature Reviews Genetics.

[20]  Marie C. M. Lin,et al.  Transcriptional and epigenetic regulation of human microRNAs. , 2013, Cancer letters.

[21]  Yuan Yang,et al.  Microarray profiling of microRNAs expressed in testis tissues of developing primates , 2009, Journal of Assisted Reproduction and Genetics.

[22]  D. Montjean,et al.  Sperm transcriptome profiling in oligozoospermia , 2011, Journal of Assisted Reproduction and Genetics.

[23]  Robert Blelloch,et al.  Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. , 2008, Genes & development.

[24]  P. Khatri,et al.  Spermatozoal RNA profiles of normal fertile men , 2002, The Lancet.

[25]  A. Gyenesei,et al.  Transcriptome Profiling of the Murine Testis during the First Wave of Spermatogenesis , 2013, PloS one.

[26]  Zuoren Yu,et al.  MicroRNA Mirn122a Reduces Expression of the Posttranscriptionally Regulated Germ Cell Transition Protein 2 (Tnp2) Messenger RNA (mRNA) by mRNA Cleavage1 , 2005, Biology of reproduction.

[27]  Hongbing Shen,et al.  Seminal plasma microRNAs: potential biomarkers for spermatogenesis status. , 2012, Molecular human reproduction.

[28]  U. Heinemann,et al.  Mechanisms of Lin28-Mediated miRNA and mRNA Regulation—A Structural and Functional Perspective , 2013, International journal of molecular sciences.

[29]  X. Chen,et al.  Altered profile of seminal plasma microRNAs in the molecular diagnosis of male infertility. , 2011, Clinical chemistry.

[30]  René F. Ketting,et al.  PIWI-interacting RNAs: from generation to transgenerational epigenetics , 2013, Nature Reviews Genetics.

[31]  J. Hua,et al.  miR‐34c works downstream of p53 leading to dairy goat male germline stem‐cell (mGSCs) apoptosis , 2013, Cell proliferation.

[32]  J. Toppari,et al.  Dicer Is Required for Haploid Male Germ Cell Differentiation in Mice , 2011, PloS one.

[33]  R. Sharpe Sperm counts and fertility in men: a rocky road ahead , 2012, EMBO reports.

[34]  D. Sinclair,et al.  Germline energetics, aging, and female infertility. , 2013, Cell metabolism.

[35]  Zhiyv Niu,et al.  MicroRNA-21 regulates the self-renewal of mouse spermatogonial stem cells , 2011, Proceedings of the National Academy of Sciences.

[36]  P. Cohen,et al.  AGO4 regulates entry into meiosis and influences silencing of sex chromosomes in the male mouse germline. , 2012, Developmental cell.

[37]  P. Khaitovich,et al.  Birth and expression evolution of mammalian microRNA genes , 2013, Genome research.

[38]  B. Nixon,et al.  miRNA and mammalian male germ cells. , 2012, Human reproduction update.

[39]  R. Aharonov,et al.  MicroRNAs accurately identify cancer tissue origin , 2008, Nature Biotechnology.

[40]  D. Bartel MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[41]  H. Scherthan,et al.  Dicer is required for Sertoli cell function and survival. , 2010, The International journal of developmental biology.

[42]  Michael Q. Zhang,et al.  Critical roles for Dicer in the female germline. , 2007, Genes & development.

[43]  Wei Yan,et al.  Incomplete cre‐mediated excision leads to phenotypic differences between Stra8‐iCre; Mov10l1lox/lox and Stra8‐iCre; Mov10l1lox/Δ mice , 2013, Genesis.

[44]  J. Vonesch,et al.  Preparation, isolation and characterization of stage-specific spermatogenic cells for cellular and molecular analysis , 2004, Nature Methods.

[45]  Yongxin Ma,et al.  A microarray for microRNA profiling in mouse testis tissues. , 2007, Reproduction.

[46]  H. Kaessmann,et al.  Dicer1 Depletion in Male Germ Cells Leads to Infertility Due to Cumulative Meiotic and Spermiogenic Defects , 2011, PloS one.

[47]  S. Sangiao-Alvarellos,et al.  Distinct expression patterns predict differential roles of the miRNA-binding proteins, Lin28 and Lin28b, in the mouse testis: studies during postnatal development and in a model of hypogonadotropic hypogonadism. , 2013, Endocrinology.

[48]  T. Mikkelsen,et al.  Cellular source and mechanisms of high transcriptome complexity in the mammalian testis. , 2013, Cell reports.

[49]  M. Primig,et al.  Global human tissue profiling and protein network analysis reveals distinct levels of transcriptional germline-specificity and identifies target genes for male infertility. , 2012, Human reproduction.

[50]  J. Segars,et al.  Are there subtle genome-wide epigenetic alterations in normal offspring conceived by assisted reproductive technologies? , 2011, Fertility and sterility.

[51]  R. Sullivan,et al.  microRNA signature is altered in both human epididymis and seminal microvesicles following vasectomy. , 2013, Human reproduction.

[52]  Wei Yan,et al.  Control of messenger RNA fate by RNA-binding proteins: an emphasis on mammalian spermatogenesis. , 2012, Journal of andrology.

[53]  M. Griswold,et al.  Two miRNA Clusters, Mir-17-92 (Mirc1) and Mir-106b-25 (Mirc3), Are Involved in the Regulation of Spermatogonial Differentiation in Mice1 , 2012, Biology of reproduction.

[54]  J. Overstreet,et al.  Best practice policies for male infertility. , 2002, The Journal of urology.

[55]  M. Bergmann,et al.  The pluripotency factor LIN28 in monkey and human testes: a marker for spermatogonial stem cells? , 2012, Molecular human reproduction.

[56]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[57]  W. Cheng,et al.  Microarray analysis of microRNA expression patterns in the semen of infertile men with semen abnormalities. , 2012, Molecular medicine reports.

[58]  J. Hua,et al.  miR‐34c Enhances Mouse Spermatogonial Stem Cells Differentiation by Targeting Nanos2 , 2014, Journal of cellular biochemistry.

[59]  Lian Hu,et al.  Identification of microRNAs predominately derived from testis and epididymis in human seminal plasma. , 2014, Clinical biochemistry.

[60]  N. Kotaja,et al.  Small RNAs in spermatogenesis , 2013, Molecular and Cellular Endocrinology.

[61]  Charles E. Vejnar,et al.  Loss of Dicer in Sertoli Cells Has a Major Impact on the Testicular Proteome of Mice , 2010, Molecular & Cellular Proteomics.

[62]  K. Kaestner,et al.  The pluripotency factor LIN28 marks undifferentiated spermatogonia in mouse , 2009, BMC Developmental Biology.

[63]  Danielle M. Santarelli,et al.  A Unique Combination of Male Germ Cell miRNAs Coordinates Gonocyte Differentiation , 2012, PloS one.

[64]  S. Meachem,et al.  Hormonal regulation of male germ cell development. , 2010, The Journal of endocrinology.

[65]  Howard Y. Chang,et al.  Genome regulation by long noncoding RNAs. , 2012, Annual review of biochemistry.

[66]  A. Amon,et al.  Meiosis I: when chromosomes undergo extreme makeover. , 2013, Current opinion in cell biology.

[67]  M. Gorospe,et al.  Interaction between microRNAs and actin-associated protein Arpc5 regulates translational suppression during male germ cell differentiation , 2012, Proceedings of the National Academy of Sciences.

[68]  R. Braun,et al.  LIN28A Marks the Spermatogonial Progenitor Population and Regulates Its Cyclic Expansion , 2014, Stem cells.

[69]  Michael T. McManus,et al.  Dicer1 Is Required for Differentiation of the Mouse Male Germline1 , 2008, Biology of reproduction.

[70]  Christina Backes,et al.  MicroRNA expression profiles in human testicular tissues of infertile men with different histopathologic patterns. , 2014, Fertility and sterility.

[71]  Yuanwei Zhang,et al.  MicroRNA and piRNA Profiles in Normal Human Testis Detected by Next Generation Sequencing , 2013, PloS one.

[72]  C. Payne,et al.  MicroRNA 146 (Mir146) Modulates Spermatogonial Differentiation by Retinoic Acid in Mice1 , 2013, Biology of reproduction.

[73]  Wei Yan,et al.  Computer-Assisted Annotation of Murine Sertoli Cell Small RNA Transcriptome1 , 2013, Biology of reproduction.

[74]  Stephen A Krawetz,et al.  Success and failure in human spermatogenesis as revealed by teratozoospermic RNAs. , 2007, Human molecular genetics.

[75]  Frédéric Chalmel,et al.  The conserved transcriptome in human and rodent male gametogenesis , 2007, Proceedings of the National Academy of Sciences.

[76]  R. Blelloch,et al.  MicroRNA Function Is Globally Suppressed in Mouse Oocytes and Early Embryos , 2010, Current Biology.

[77]  Selene L. Fernandez-Valverde,et al.  MicroRNAs-140-5p/140-3p Modulate Leydig Cell Numbers in the Developing Mouse Testis1 , 2013, Biology of reproduction.

[78]  R. Braun,et al.  DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration , 2011, Nature.

[79]  Y. Matsui The molecular mechanisms regulating germ cell development and potential. , 2010, Journal of andrology.

[80]  M. Kanatsu-Shinohara,et al.  Spermatogonial stem cell self-renewal and development. , 2013, Annual review of cell and developmental biology.

[81]  Tim Savage,et al.  Childhood outcomes of assisted reproductive technology. , 2011, Human reproduction.

[82]  L. Sistonen,et al.  miR-18, a member of Oncomir-1, targets heat shock transcription factor 2 in spermatogenesis , 2010, Development.

[83]  N. Perrimon,et al.  An endogenous small interfering RNA pathway in Drosophila , 2008, Nature.

[84]  W. Filipowicz,et al.  The widespread regulation of microRNA biogenesis, function and decay , 2010, Nature Reviews Genetics.

[85]  Robert I McLachlan,et al.  Hormonal regulation of sertoli cell micro-RNAs at spermiation. , 2011, Endocrinology.

[86]  S. Cui,et al.  MicroRNA-34c Enhances Murine Male Germ Cell Apoptosis through Targeting ATF1 , 2012, PloS one.

[87]  E. Marcon,et al.  miRNA and piRNA localization in the male mammalian meiotic nucleus , 2008, Chromosome Research.

[88]  K. Lao,et al.  Sperm-borne microRNA-34c is required for the first cleavage division in mouse , 2011, Proceedings of the National Academy of Sciences.

[89]  R. Morimoto,et al.  Heat shock factors: integrators of cell stress, development and lifespan , 2010, Nature Reviews Molecular Cell Biology.

[90]  C. Rathke,et al.  Chromatin dynamics during spermiogenesis. , 2014, Biochimica et biophysica acta.

[91]  Sanghyuk Lee,et al.  MicroRNA genes are transcribed by RNA polymerase II , 2004, The EMBO journal.

[92]  Michael T. McManus,et al.  Sertoli cell Dicer is essential for spermatogenesis in mice. , 2009, Developmental biology.

[93]  Wei Yan,et al.  Cloning and expression profiling of testis-expressed microRNAs. , 2007, Developmental biology.

[94]  Luís Rato,et al.  Metabolic regulation is important for spermatogenesis , 2012, Nature Reviews Urology.

[95]  Paolo Sassone-Corsi,et al.  Chromatin remodelling and epigenetic features of germ cells , 2005, Nature.

[96]  C. Tsai-Morris,et al.  Testis-specific miRNA-469 Up-regulated in Gonadotropin-regulated Testicular RNA Helicase (GRTH/DDX25)-null Mice Silences Transition Protein 2 and Protamine 2 Messages at Sites within Coding Region , 2011, The Journal of Biological Chemistry.

[97]  S. Krawetz,et al.  Stability, delivery and functions of human sperm RNAs at fertilization , 2013, Nucleic acids research.

[98]  Qi-En Yang,et al.  MicroRNAs 221 and 222 regulate the undifferentiated state in mammalian male germ cells , 2013, Development.

[99]  Wei Yan,et al.  Many X-linked microRNAs escape meiotic sex chromosome inactivation , 2009, Nature Genetics.

[100]  L. Castellano,et al.  Deep sequencing of small RNAs identifies canonical and non-canonical miRNA and endogenous siRNAs in mammalian somatic tissues , 2013, Nucleic acids research.

[101]  Wei Yan,et al.  The Rnase Iii Enzyme Drosha Is Essential for Microrna Production and Spermatogenesis * □ S , 2022 .

[102]  Wei Yan,et al.  Male germ cells express abundant endogenous siRNAs , 2011, Proceedings of the National Academy of Sciences.

[103]  J. Sun,et al.  Long Non-Coding RNA Expression Profiling of Mouse Testis during Postnatal Development , 2013, PloS one.

[104]  R. Braun,et al.  Deregulated Sex Chromosome Gene Expression with Male Germ Cell-Specific Loss of Dicer1 , 2012, PloS one.

[105]  T. Johanson,et al.  MicroRNA-independent roles of the RNase III enzymes Drosha and Dicer , 2013, Open Biology.

[106]  M. Griswold,et al.  Expression of Mirlet7 Family MicroRNAs in Response to Retinoic Acid-Induced Spermatogonial Differentiation in Mice1 , 2011, Biology of reproduction.

[107]  P. Zamore,et al.  Small silencing RNAs: an expanding universe , 2009, Nature Reviews Genetics.

[108]  H. Stoop,et al.  Expression and interdependencies of pluripotency factors LIN28, OCT3/4, NANOG and SOX2 in human testicular germ cells and tumours of the testis. , 2011, International journal of andrology.

[109]  J. Samarut,et al.  Role of miR-34c microRNA in the late steps of spermatogenesis. , 2010, RNA.

[110]  P. Sassone-Corsi,et al.  Opinion: The chromatoid body: a germ-cell-specific RNA-processing centre , 2007, Nature Reviews Molecular Cell Biology.

[111]  Yidong Chen,et al.  Androgen-Responsive MicroRNAs in Mouse Sertoli Cells , 2012, PloS one.

[112]  Cizhong Jiang,et al.  MicroRNA-449 and MicroRNA-34b/c Function Redundantly in Murine Testes by Targeting E2F Transcription Factor-Retinoblastoma Protein (E2F-pRb) Pathway* , 2012, The Journal of Biological Chemistry.

[113]  S. Drăghici,et al.  A survey of small RNAs in human sperm. , 2011, Human reproduction.

[114]  D. D. de Rooij,et al.  Molecular control of rodent spermatogenesis. , 2012, Biochimica et biophysica acta.

[115]  M. Azim Surani,et al.  MicroRNA Biogenesis Is Required for Mouse Primordial Germ Cell Development and Spermatogenesis , 2008, PloS one.

[116]  J. Gatti,et al.  The epididymal transcriptome and proteome provide some insights into new epididymal regulations. , 2011, Journal of andrology.

[117]  C. Huang,et al.  RESEARCH ARTICLE Open Access Research article Inactivation of Dicer1 in Steroidogenic factor 1-positive cells reveals tissue-specific requirement for Dicer1 in adrenal, testis, and ovary , 2022 .

[118]  Eric C. Lai,et al.  Endogenous small interfering RNAs in animals , 2008, Nature Reviews Molecular Cell Biology.

[119]  Elizabeth Noonan,et al.  World Health Organization reference values for human semen characteristics. , 2010, Human reproduction update.

[120]  Hongbing Shen,et al.  Genome-wide microRNA expression profiling in idiopathic non-obstructive azoospermia: significant up-regulation of miR-141, miR-429 and miR-7-1-3p. , 2013, Human reproduction.

[121]  Paolo Sassone-Corsi,et al.  The chromatoid body of male germ cells: similarity with processing bodies and presence of Dicer and microRNA pathway components. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[122]  Wei Yan,et al.  Tissue-dependent paired expression of miRNAs , 2007, Nucleic acids research.

[123]  D. G. Rooij,et al.  All you wanted to know about spermatogonia but were afraid to ask. , 2000, Journal of andrology.

[124]  C. Sette,et al.  Role of RNA-binding proteins in mammalian spermatogenesis. , 2010, International journal of andrology.

[125]  P. Koopman,et al.  Mouse germ cell development: From specification to sex determination , 2010, Molecular and Cellular Endocrinology.

[126]  Oliver H. Tam,et al.  Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes , 2008, Nature.

[127]  Oliver H. Tam,et al.  Characterization of Dicer-deficient murine embryonic stem cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[128]  Y. Sakaki,et al.  Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes , 2008, Nature.