Sperm-borne miRNAs and endo-siRNAs are important for fertilization and preimplantation embryonic development

Abstract

Although it is believed that mammalian sperm carry small noncoding RNAs (sncRNAs) into oocytes during fertilization, it remains unknown whether these sperm-borne sncRNAs truly have any function during fertilization and preimplantation embryonic development. Germlinespecific Dicer and Drosha conditional knockout (cKO) mice produce gametes (i.e. sperm and oocytes) partially deficient in miRNAs and/or endo-siRNAs, thus providing a unique opportunity for testing whether normal sperm ( paternal) or oocyte (maternal) miRNA and endosiRNA contents are required for fertilization and preimplantation development. Using the outcome of intracytoplasmic sperm injection (ICSI) as a readout, we found that sperm with altered miRNA and endo-siRNA profiles could fertilize wild-type (WT) eggs, but embryos derived from these partially sncRNA-deficient sperm displayed a significant reduction in developmental potential, which could be rescued by injecting WT sperm-derived total or small RNAs into ICSI embryos. Disrupted maternal transcript turnover and failure in early zygotic gene activation appeared to associate with the aberrant miRNA profiles in Dicer and Drosha cKO spermatozoa. Overall, our data support a crucial function of paternal miRNAs and/or endosiRNAs in the control of the transcriptomic homeostasis in fertilized eggs, zygotes and two-cell embryos. Given that supplementation of sperm RNAs enhances both the developmental potential of preimplantation embryos and the live birth rate, it might represent a novel means to improve the success rate of assisted reproductive technologies in fertility clinics.

SpermBase: A Database for Sperm-Borne RNA Contents

“…Despite the cessation of transcription and shedding of the cytoplasm at the final stages of spermiogenesis, mature spermatozoa have been shown to possess diverse populations of both small and large RNAs [1–5]. These RNA populations, along with the paternal genome, can be delivered into the oocyte during fertilization, where they can persist beyond zygotic genome activation [5, 6].…”

“…These RNA populations, along with the paternal genome, can be delivered into the oocyte during fertilization, where they can persist beyond zygotic genome activation [5, 6]. Since their discovery in 1989, sperm-borne RNAs have been shown to function in spermatogenesis and during fertilization and early embryonic development, suggesting that they are not merely the remnants of sperm development [4, 7–10].…”

Small RNA in situ hybridization in Caenorhabditis elegans, combined with RNA-seq, identifies germline-enriched microRNAs

“…In humans, the enhancement of somatic fates by the let-7 miRNA family works in opposition to miR-372 , which promotes human germ cell fates in embryonic stem cells (Tran et al, 2016), while in mice, sperm, as well as oocytes, transmit miRNAs and endo-siRNAs critical to the developing embryo (Yuan et al, 2016). …”

Transgenerational paternal transmission of acquired traits: stress-induced modification of the sperm regulatory transcriptome and offspring phenotypes

“…While there remains much to be discovered about the biological role of microRNAs, evidence supports an expansion of the previously assumed function of sperm microRNAs in fertilisation and preimplantation embryonic development [33]. MicroRNAs must now be considered as long-term regulators of offspring behavior and stress response.…”