Advances in PIWI-piRNA function in female reproduction in mammals

Abstract

PIWI-interacting RNAs (piRNAs), which associate with PIWI clade Argonaute proteins to form piRNA-induced silencing complexes (piRISCs) in germline cells, are responsible for maintaining genomic integrity and reproductive function through transcriptional or post-transcriptional suppression of transposable elements and regulation of protein-coding genes. Recent discoveries of crucial PIWI-piRNA functions in oogenesis and embryogenesis in golden hamsters suggest an indispensable role in female fertility that has been obscured in the predominant mouse model of PIWI-piRNA pathway regulation. In particular, studies of piRNA expression dynamics, functional redundancies, and compositional variations across mammal species have advanced our understanding of piRNA functions in male and, especially, female reproduction. These findings further support the use of hamsters as a more representative model of piRNA biology in mammals. In addition to discussing these new perspectives, the current review also covers emerging directions for piRNA research, its implications for female fertility, and our fundamental understanding of reproductive mechanisms.

1. Introduction

During gametogenesis and early embryogenesis in animals, transposon elements (TEs) are actively transcribed as a result of epigenetic reprogramming, which can cause severe damage to the host genome [1–4]. In most animals, genome integrity is guided by a conserved adaptive immune system known as the PIWI-interacting RNAs (piRNAs) pathway in the germline [5–7]. piRNAs are an animal-specific class of small non-coding RNAs that are distinct from microRNAs (miRNAs) and small interfering RNAs (siRNAs) [8–12]. piRNAs guide PIWI clade Argonautes (PIWI proteins) rather than AGO clade proteins, which are known to mediate miRNA- and siRNA-dependent regulatory pathways [13]. PIWI-piRNA complexes, namely, piRNA-induced silencing complexes (piRISCs), primarily function in silencing TEs at both the transcriptional and post-transcriptional levels in animal germ cells [5,6]. Moreover, increasing evidence suggests that the PIWI-piRNA machinery can also mediate the regulation of protein-coding genes [14,15]. These critical activities of piRNAs in germ cells are indispensable for fertility in most animals [7].

In mice, which have served for decades as a common mammalian model for studying PIWI-piRNAs, the disruption of any Piwi genes or other genes critical for piRNA biogenesis leads to the arrest of spermatogenesis but does not impair oogenesis or female fertility [10,16–20]. However, recent evidence indicates that small non-coding RNAs in mouse oocytes may not be representative of other mammals, including humans [21,22], as previously thought. In particular, recent studies in golden hamsters have shown that piRNAs are essential for female fertility and that the absence of any piRNA population can lead to arrested embryonic development [23–26]. It is thus apparent that the piRNA pathway plays essential roles in female reproduction, which has long been underappreciated and warrants careful examination in other mammals. Here, we discuss recent advances in our understanding of the biological functions of the piRNA pathway in mammalian oocytes and early embryos, especially with a focus on golden hamsters and humans.