title: Germ cell-specific targeting of DICER or DGCR8 reveals a novel role for endo-siRNAs in the progression of mammalian spermatogenesis and male fertility.
abstract: Small non-coding RNAs act as critical regulators of gene expression and are essential for male germ cell development and spermatogenesis. Previously, we showed that germ cell-specific inactivation of Dicer1, an endonuclease essential for the biogenesis of micro-RNAs (miRNAs) and endogenous small interfering RNAs (endo-siRNAs), led to complete male infertility due to alterations in meiotic progression, increased spermatocyte apoptosis and defects in the maturation of spermatozoa. To dissect the distinct physiological roles of miRNAs and endo-siRNAs in spermatogenesis, we compared the testicular phenotype of mice with Dicer1 or Dgcr8 depletion in male germ cells. Dgcr8 mutant mice, which have a defective miRNA pathway while retaining an intact endo-siRNA pathway, were also infertile and displayed similar defects, although less severe, to Dicer1 mutant mice. These included cumulative defects in meiotic and haploid phases of spermatogenesis, resulting in oligo-, terato-, and azoospermia. In addition, we found by RNA sequencing of purified spermatocytes that inactivation of Dicer1 and the resulting absence of miRNAs affected the fine tuning of protein-coding gene expression by increasing low level gene expression. Overall, these results emphasize the essential role of miRNAs in the progression of spermatogenesis, but also indicate a role for endo-siRNAs in this process.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Zimmermann
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Romero
authors.affiliation: Center for Integrative Genomics, University of Lausanne and Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Warnefors
authors.affiliation: Center for Integrative Genomics, University of Lausanne and Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Adem
authors.initials: A
authors.lastname: Bilican
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Christelle
authors.initials: C
authors.lastname: Borel
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Lee B
authors.initials: LB
authors.lastname: Smith
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Noora
authors.initials: N
authors.lastname: Kotaja
authors.affiliation: Center for Integrative Genomics, University of Lausanne and Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Henrik
authors.initials: H
authors.lastname: Kaessmann
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Serge
authors.initials: S
authors.lastname: Nef
mesh_terms: D000818:Animals; D005298:Fertility / Q000235:genetics*; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000378:metabolism*; D013737:Testis / Q000378:metabolism
chemical_list: C474044:Dgcr8 protein, mouse; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D043244:Ribonuclease III