Dicer Is Required for Haploid Male Germ Cell Differentiation in Mice

Abstract

BackgroundThe RNase III endonuclease Dicer is an important regulator of gene expression that processes microRNAs (miRNAs) and small interfering RNAs (siRNAs). The best-characterized function of miRNAs is gene repression at the post-transcriptional level through the pairing with mRNAs of protein-encoding genes. Small RNAs can also act at the transcriptional level by controlling the epigenetic status of chromatin. Dicer and other mediators of small RNA pathways are present in mouse male germ cells, and several miRNAs and endogenous siRNAs are expressed in the testis, suggesting that Dicer-dependent small RNAs are involved in the control of the precisely timed and highly organised process of spermatogenesis.Principal FindingsBeing interested in the Dicer-mediated functions during spermatogenesis, we have analysed here a male germ cell-specific Dicer1 knockout mouse model, in which the deletion of Dicer1 takes place during early postnatal development in spermatogonia. We found that Dicer1 knockout testes were reduced in size and spermatogenesis within the seminiferous tubules was disrupted. Dicer1 knockout epididymides contained very low number of mature sperm with pronounced morphological abnormalities. Spermatogonial differentiation appeared unaffected. However, the number of haploid cells was decreased in knockout testes, and an increased number of apoptotic spermatocytes was observed. The most prominent defects were found during late haploid differentiation, and Dicer was demonstrated to be critical for the normal organization of chromatin and nuclear shaping of elongating spermatids.Conclusions/SignificanceWe demonstrate that Dicer and Dicer-dependent small RNAs are imperative regulators of haploid spermatid differentiation and essential for male fertility.

The role of epigenetics in idiopathic male infertility

“…miRNAs and endo-siRNAs are abundantly expressed in male germ cells throughout spermatogenesis, whereas piRNAs are only present in spermatocytes at the pachytene stage and in round spermatids [92,94]. The absolute requirement for miRNAs and endo-siRNAs for spermatogenesis has been shown by two initial studies where Dicer1 gene was knocked out in two different mouse models [95,96]. Germ-cell specific deletion of Dicer1 in these models has led to complete male infertility due to alterations in meiotic progression, increased spermatocyte apoptosis, and failure of haploid male germ cell differentiation.…”

MicroRNAs and DNA methylation as epigenetic regulators of mitosis, meiosis and spermiogenesis

“…Sertoli cellspecific deletion of Dicer, a central component of the RNAi machinery, severely impairs Sertoli cell competence, leading to male infertility due to the absence of mature spermatozoa and testicular degeneration (Papaioannou et al 2009), reflecting an important role of the Dicer for male germ cell development. Germ cellspecific deletion of Dicer1 leads to overexpression of genes for meiotic sex chromosome inactivation (MSCI), an increase in spermatocyte apoptosis and defects in chromatin organization and nuclear shaping of elongating spermatids (Korhonen et al 2011, Greenlee et al 2012, Zimmermann et al 2014, suggesting that Dicer1 is required for the meiotic and haploid phases of spermatogenesis. In addition to Dicer, DGCR8 has been shown to be indispensable for the biogenesis of miRNAs but not endo-siRNAs, and similar symptom occurs in the conditional DGCR8-knockout mice, although the phenotype is less severe compared to the Dicer1-knockout mice (Zimmermann et al 2014).…”

Expressions of miR-15a and its target gene HSPA1B in the spermatozoa of patients with varicocele

“…DICER1 is a cytoplasmic RNase III endonuclease that is essential for miRNA biogenesis as it cleaves the precursor miRNAs to produce mature miRNAs (Inui et al 2010). Loss of Dicer1 in mouse postnatal male germ cells leads to infertility due to disruptions in the meiotic and postmeiotic stages (Korhonen et al 2011, Greenlee et al 2012, suggesting that miRNAs play important roles in spermatogenesis. Moreover, altered miRNAs expressions of the ejaculated spermatozoa in patients with different spermatogenic impairments have been demonstrated by microarray (Lian et al 2009, Abu-Halima et al 2013.…”