{"doi":"10.1093/biolre/ioab206","title":"Cracking the egg: A breakthrough in piRNA function in mammalian oocytes and embryos","abstract":"Piwi-interacting RNAs (piRNAs) are a class of small regulatory RNAs that safeguard the genome and control gene expression in the germline [1]. Guiding associated PIWI proteins, piRNAs play conserved roles in silencing transposable elements (TEs) and ensuring animal fertility in both sexes [1]. In mammals, however, it has been enigmatic why the piRNA pathway lacks an apparent function in female reproduction. This is because genetic studies have been exclusively conducted in mouse models and mutations of various piRNA pathway genes in mice cause only male-specific sterility. Even female mice with the ablation of all three Piwi genes are fertile [2]. Interestingly, emerging evidence suggests mice could be an outlier as a mammalian model. PIWI proteins and piRNAs are abundantly expressed in the female germline of all mammals examined [3–6]. Most mammals including farm animals, monkeys, humans, and even non-murine rodents have four Piwi genes (Piwil1, Piwil2, Piwil3, and Piwil4). Mice by contrast only possess three, lacking Piwil3, a gene with female germ cell-specific expression (Figure 1A). In addition, the presence of a robust oocyte-specific endo-siRNA pathway in mice might mask the dependence on piRNAs in the female germline [7–9]. Do mammalian piRNAs have any function in females? Using golden hamsters as an alternative mammalian model, three recent studies published in Nature Cell Biology by Hasuwa et al., Loubalova et al., and Zhang et al. have solved this long-lasting puzzle by reporting a critical function of the piRNA pathway in mammalian female fertility and embryogenesis [10–12]. The PIWI/piRNA system in golden hamsters. (A) The lack of Piwil3 gene in the mouse genome. (B) The presence of PIWI proteins and associated piRNAs in the golden hamster testis and ovary. (C) Effect of disruption of piRNA pathway genes Piwil1, Piwill3, or Mov10l1 on male germ cell development in golden hamsters. Spg: spermatogonium; LS: leptotene spermatocyte; PS: pachytene spermatocyte; RS: round spermatid; ES: elongating spermatid. (D) Effect of disruption of piRNA pathway genes Piwil1, Piwll3, or Mov10l1 on female germ cell development and embryogenesis in golden hamsters. GV: germinal vesicle oocyte; MII: metaphase II oocyte. To interrogate the function of the piRNA pathway in golden hamsters, three groups exploited CRISPR-Cas9 genome editing to disrupt hamster Piwi genes or a piRNA biogenesis factor. Hasuwa et al. deleted Piwil1 and Piwil3; Loubalova et al. mutated piRNA biogenesis factor Mov10l1; and Zhang et al. disrupted Piwil1 and Mov10l1 in golden hamsters [10–12]. Similar to male knockout mice [13–15], male hamsters deficient in MOV10L1 or PIWIL1 are sterile due to spermatogenic arrest [10–12] (Figure 1C). Particularly, stages of germ cell arrest show degree of differences between mice and hamsters [10–12]. As expected, PIWIL3-deficient male hamsters are fertile, consistent with its lack of expression in the male gonad [10] (Figure 1C). Strikingly, female hamsters lacking MOV10L1 or PIWIL1 are completely sterile, and PIWIL3-deficient females exhibit subfertility [10–12] (Figure 1D). This is in stark contrast to the dispensability of the piRNA pathway genes in mouse models and reveals for the first time the disruption of the piRNA pathway indeed affects female fertility in mammals. Notably, in all three mutants, ovary development and oogenesis appear normal. Oocytes produced are fertilizable by wild-type sperm, but embryo developmental arrest occurs at distinct stages (Figure 1D). Three major populations of piRNAs (19, 23, and 29 nt) are dynamically expressed in golden hamster oocytes and embryos, corresponding to PIWIL1-bound 23 nt/29 nt and PIWIL3-bound 19-nt piRNAs, respectively (Figure 1B). Disruption of Mov10l1 severely ablates all three populations of piRNAs in hamster oocytes and unleashes LINE1 and LTR retrotransposon overexpression [11, 12]. This suggests that at least some TE-related piRNAs play an active role in transposon s","journal":"Biology of Reproduction","year":2021,"id":185754,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":278161,"name":"Chen Chen","orcid":"0000-0002-9748-3111","position":1,"is_corresponding":false},{"id":483631,"name":"Deqiang Ding","orcid":"0000-0002-7959-5654","position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-18T23:48:38.805613Z","pmid":"34725680","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}