The nuage mediates retrotransposon silencing in mouse primordial ovarian follicles

Abstract

SUMMARYMobilization of endogenous retrotransposons can destabilize the genome, an imminent danger during epigenetic reprogramming of cells in the germline. The P-element-induced wimpy testis (PIWI)-interacting RNA (piRNA) pathway is known to silence retrotransposons in the mouse testes. Several piRNA pathway components localize to the unique, germline structure known as the nuage. In this study, we surveyed mouse ovaries and found, for the first time, transient appearance of nuage-like structures in oocytes of primordial follicles. Mouse vasa homolog (MVH), Piwi-like 2 (PIWIL2/MILI) and tudor domain-containing 9 (TDRD9) are present in these structures, whereas aggregates of germ cell protein with ankyrin repeats, sterile alpha motif and leucine zipper (GASZ) localize separately in the cytoplasm. Retrotransposons are silenced in primordial ovarian follicles, and de-repressed upon reduction of piRNA expression in Mvh, Mili or Gasz mutants. However, these null-mutant females, unlike their male counterparts, are fertile, uncoupling retrotransposon activation from sterility.

Multiple LINEs of retrotransposon silencing mechanisms in the mammalian germline

“…Intriguingly, several piRNA pathway proteins such as DDX4, MILI, TDRD9 and GASZ are expressed in mouse oocytes [91]. Furthermore, in null mutants for each of these proteins, LINE1 is upregulated in the primordial follicles of the ovary, similar to observations in male germ cells [91].…”

Posttranscriptional Regulation of Gene Expression by Piwi Proteins and piRNAs

“…For example, more than one quarter of mouse (27.7%) and human (28.5%) Refseqs possess at least one retrotransposon in their 3’ UTRs. In zebrafish, Xenopus and mouse oocytes, Piwi proteins and piRNAs are mainly found in the cytoplasm, and they are involved in the suppression of retrotransposons (Houwing et al, 2007; Lau et al, 2009; Lim et al, 2013; Watanabe et al, 2008). These observations suggest that retrotransposons are suppressed by piRNA pathway post-transcriptionally in vertebrate oocytes.…”

“…In mouse oocytes, insertion of transposon sequences confers instability to reporter mRNAs (Watanabe et al, 2006). A recent study revealed that some transposon-driven mRNAs harboring transposon sequences in their 5’ UTRs are upregulated in Mvh, Mili, and Gasz mutant oocytes (Lim et al, 2013). These observations suggest that these transposon-driven mRNAs are directly regulated by piRNAs through the transposon sequences in their 5’ UTRs.…”

“…However, how and how much increased transposon expression contribute to cell death or other defects remains to be answered. Although piRNAs are involved in post-transcriptional transposon suppression in mouse oocytes, oocytes mutant for the Piwi-piRNA pathway do not show any visible defects (Lim et al, 2013; Watanabe et al, 2008). Presumably, the consequence of failed suppression in the mutants may only become apparent in future generations.…”

“…In addition, they regulate transposon expression at the transcriptional level by inducing repressive epigenetic marks such as histone H3K9me3 and DNA methylation, which has been well summarized by several reviews and thus will not be the focus of this review (Castel and Martienssen, 2013; Luteijn and Ketting, 2013; Olovnikov et al, 2012; Peng and Lin, 2013; Ross et al, 2014). Beyond transcriptional regulation, a growing number of studies have suggested that piRNAs are involved in the post-transcriptional regulation of not only transposon RNAs but also other types of RNAs including mRNAs and RNA viruses (Gou et al, 2014; Kiuchi et al, 2014; Kotelnikov et al, 2009; Lim et al, 2013; Morazzani et al, 2012; Rouget et al, 2010). This is often accomplished by using transposon sequences as regulatory elements.…”