The RNase III Enzyme DROSHA Is Essential for MicroRNA Production and Spermatogenesis

The RNase III Enzyme DROSHA Is Essential for MicroRNA Production and Spermatogenesis

Background: miRNA biogenesis requires two RNase III enzymes, DROSHA and DICER. Results: Lack of DROSHA in the male germ line leads to deficiency in miRNA production and male infertility. Conclusion: DROSHA and DICER have both common and unique functions in male germ cell development. Significance: T...

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Published in:The Journal of biological chemistry Vol. 287; no. 30; pp. 25173 - 25190
Main Authors: Wu, Qiuxia, Song, Rui, Ortogero, Nicole, Zheng, Huili, Evanoff, Ryan, Small, Chris L., Griswold, Michael D., Namekawa, Satoshi H., Royo, Helene, Turner, James M., Yan, Wei
Format: Journal Article
Language:English
Published: United States Elsevier Inc 20-07-2012
American Society for Biochemistry and Molecular Biology
Subjects:
Animals
Azoospermia - enzymology
DEAD-box RNA Helicases - genetics
DEAD-box RNA Helicases - metabolism
Fertility - physiology
Male
Mice
Mice, Knockout
MicroRNA
MicroRNAs - genetics
MicroRNAs - metabolism
Oligospermia - enzymology
Oligospermia - genetics
Ribonuclease III - genetics
Ribonuclease III - metabolism
RNA
RNA Interference (RNAi)
RNA Processing
Small Nucleolar RNA (snoRNA)
Spermatids - enzymology
Spermatocytes - enzymology
Spermatogenesis
Spermatogenesis - physiology
Testis - enzymology
Testis - growth & development
MicroRNA
Spermatogenesis
RNA Processing
RNA Interference (RNAi)
Small Nucleolar RNA (snoRNA)
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Summary:Background: miRNA biogenesis requires two RNase III enzymes, DROSHA and DICER. Results: Lack of DROSHA in the male germ line leads to deficiency in miRNA production and male infertility. Conclusion: DROSHA and DICER have both common and unique functions in male germ cell development. Significance: This study reveals an essential role of DROSHA, DICER, and DROSHA-/DICER-dependent small noncoding RNAs spermatogenesis. DROSHA is a nuclear RNase III enzyme responsible for cleaving primary microRNAs (miRNAs) into precursor miRNAs and thus is essential for the biogenesis of canonical miRNAs. DICER is a cytoplasmic RNase III enzyme that not only cleaves precursor miRNAs to produce mature miRNAs but also dissects naturally formed/synthetic double-stranded RNAs to generate small interfering RNAs (siRNAs). To investigate the role of canonical miRNA and/or endogenous siRNA production in spermatogenesis, we generated Drosha or Dicer conditional knock-out (cKO) mouse lines by inactivating Drosha or Dicer exclusively in spermatogenic cells in postnatal testes using the Cre-loxp strategy. Both Drosha and Dicer cKO males were infertile due to disrupted spermatogenesis characterized by depletion of spermatocytes and spermatids leading to oligoteratozoospermia or azoospermia. The developmental course of spermatogenic disruptions was similar at morphological levels between Drosha and Dicer cKO males, but Drosha cKO testes appeared to be more severe in spermatogenic disruptions than Dicer cKO testes. Microarray analyses revealed transcriptomic differences between Drosha- and Dicer-null pachytene spermatocytes or round spermatids. Although levels of sex-linked mRNAs were mildly elevated, meiotic sex chromosome inactivation appeared to have occurred normally. Our data demonstrate that unlike DICER, which is required for the biogenesis of several small RNA species, DROSHA is essential mainly for the canonical miRNA production, and DROSHA-mediated miRNA production is essential for normal spermatogenesis and male fertility.
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content type line 23
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112.362053