Roles of microRNAs in mammalian reproduction: from the commitment of germ cells to peri-implantation embryos

Abstract

MicroRNAs (miRNAs) are active regulators of numerous biological and physiological processes including most of the events of mammalian reproduction. Understanding the biological functions of miRNAs in the context of mammalian reproduction will allow a better and comparative understanding of fertility and sterility in male and female mammals. Herein, we summarize recent progress in miRNA-mediated regulation of mammalian reproduction and highlight the significance of miRNAs in different aspects of mammalian reproduction including the biogenesis of germ cells, the functionality of reproductive organs, and the development of early embryos. Furthermore, we focus on the gene expression regulatory feedback loops involving hormones and miRNA expression to increase our understanding of germ cell commitment and the functioning of reproductive organs. Finally, we discuss the influence of miRNAs on male and female reproductive failure, and provide perspectives for future studies on this topic.

Keywords: gametogenesis; germ layer specification; hormonal balance; mammalian reproduction; miRNAs; peri-implantation.

Figure 1

Adverse effects of the loss of microRNA (miRNA)‐processing machinery during mammalian reproduction. The loss of miRNA‐processing machinery can cause reproductive impairment to different extents, including embryonic death, based on the stage at which it is lost. However, mating behaviour of both males and females remains intact. PGC, primordial germ cell.

Figure 2

MicroRNA (miRNA) regulation at different stages of sex specification and gametogenesis. The miRNAs that are listed for different stages of oogenesis, spermatogenesis and early embryonic development are the predominantly expressed miRNAs of these stages. miRNAs are involved in every stage of early embryonic development and gametogenesis, except the period between the mature oocyte and first zygotic cell division, where the functions of miRNAs are abrogated (reported in mouse, but yet to be verified in other mammals), and then re‐established between two‐ and four‐cell stage pluripotent embryos. Loss of Dicer during the sex‐undifferentiated stage typically causes embryonic death, while primordial germ cell (PGC)‐specific loss causes the impairment and failure of migration, colonization, and commitment of sex‐specific gonads. miRNAs are highly expressed during gametogenesis, and some miRNAs have sex‐ and purpose‐specific roles; for example, miR‐124 plays an important role in female gonad commitment by suppressing Sox‐9 expression, and the loss of miR‐124 before sex commitment can cause sex reversal in females. Other miRNAs are equally important in nearly all stages; for example, miR‐21 is important in all stages of gametogenesis and is responsible for the viability and survival of cells. The expression of miR‐21 during pregnancy indicates the presence of activated and live embryo (s). CL, corpus luteum; TE, trophectoderm; KO, knockout; GV, germinal vesicle; GC, granulosa cell; DF, dominant follicle; MSCI, meiotic sex chromosome inactivation.

Figure 3

MicroRNA (miRNA) regulation in the maintenance of male hormonal balance. A panel of miRNAs regulates Pou2f1‐ and Meis1‐mediated gonadotropin‐releasing hormone signalling by targeting Zeb1, and thus these miRNAs may play important roles in the maintenance of hormonal balance. The expression of miRNAs changes with levels of different reproductive hormones; additionally, hormonal balance is reported to be miRNA‐dependent, as miRNAs regulate the proliferation, differentiation, function, and apoptosis of male steroidogenic cells. Thus, miRNAs, genes, and hormones develop a feedback loop that optimizes spermatogenesis; any imbalance in the feedback loop can result in azoospermia, oligospermia, infertility, and reproductive failure in males. FSH, follicle‐stimulating hormone; LH, luteneizing hormone; PL, prolactin; GnRH, gonadotropin‐releasing hormone; PTEN, phosphatase and tensin homolog; EPS15, epidermal growth factor receptor pathway substrate 15; AR, androgen receptor; Cebpb, CCAAT/enhancer binding protein beta; Zeb1, zinc finger E‐box binding homeobox 1; Glg1, golgi glycoprotein 1; BMP4, bone morphogenetic protein 4; Ptgfrn, prostaglandin F2 receptor inhibitor; Pou2f1, POU class 2 homeobox 1; Meis1, meis homeobox 1; Cyp11a1, cytochrome P450 family 11 subfamily A member 1; Star, steroidogenic acute regulatory protein; Nr5a1, nuclear receptor subfamily 5 group A member 1; Ldlr, low density lipoprotein receptor; Abca1, ATP binding cassette subfamily A Member 1; Abcg1, ATP binding cassette subfamily G member 1; Srebp‐1c, sterol regulatory element binding transcription factor 1; Bcl‐w, BCL2 like 2; Ccng1, cyclin G1; Foxd1, forkhead box D1; Dsc1, desmocollin 1; GLI3, GLI family zinc finger 3; RNF4, ring finger protein 4.

Figure 4

MicroRNA (miRNA) regulation in the maintenance of female hormonal balance. The proliferation, growth, differentiation, functioning, and apoptosis of female steroidogenic cells [granulosa cell (GC) and thecal cell (TC)] are highly regulated by miRNAs. miRNAs are also active regulators of female steroidogenic genes including cytochrome P450 family 19 subfamily A member 1 (Cyp19a1); steroidogenic acute regulatory protein (Star), and prostaglandin‐endoperoxide synthase 2 (Ptgs2); thus, miRNAs directly regulate the steroidogenic process in females through gonadotropin‐releasing hormone (GnRH), follicle‐stimulating hormone (FSH), and luteinizing hormone (LH) signalling. The vasculogenesis and angiogenesis of progesterone‐producing corpus lutem (CL) is also related to the expression of miRNAs, making miRNAs important regulatory molecules during the female steroidogenic processes. miRNAs are involved in both follicular steroidogenesis and luteal steroidogenesis. PGF2α, prostaglandin; COC, cumulus‐oocyte complex; E2f1, E2F transcription factor 1; Sf‐1, steroidogenic factor 1 nuclear receptor; IL‐1b, interleukin 1 beta; COX‐2, cyclooxygenase 2; INHBB, inhibin beta B subunit; Ctbp1, C‐terminal binding protein 1; Tagln2, transgelin 2; LIF, leukemia inhibitory factor; CDKN1A, cyclin dependent kinase inhibitor 1A; SP1, specificity protein 1; Foxl2, forkhead box L2; Rbms1, RNA binding motif single stranded interacting protein 1; Nurr1, nuclear receptor subfamily 4 group A member 2; Lrbp, LH receptor mRNA‐binding protein; Acvr1b, activin A receptor type 1B; XIAP, X‐linked inhibitor of apoptosis; ATM, ATM serine/threonine kinase; TGFBR1, transforming growth factor beta receptor 1; CCND2, cyclin D2; BCL‐XL, BCL2 like 1; SMAD5, SMAD family member 5; SMAD4, SMAD family member 4; BCL2, B‐cell lymphoma 2; BAX, BCL2 associated X protein; GLG1, Golgi glycoprotein 1; ZEB1, zinc finger E‐box binding homeobox 1; BMP4, bone morphogenetic protein 4; PTGFRN, prostaglandin F2 receptor inhibitor; IFNGR1, interferon gamma receptor 1.

Figure 5

MicroRNA (miRNA) regulation during implantation and germ layer specification. Based on their functions, miRNAs are categorized as anti‐ or pro‐implantation miRNAs, pluripotency miRNAs, or miRNAs that promote differentiation and commitment of mesoderm, endoderm, ectoderm, and trophectoderm lineages. Parental miRNAs might be important regulators during embryonic germ layer specification; variation in the absorption of parental miRNAs could initiate variation in differentiation potential of the inner cell mass (ICM), and thus could direct the ICM towards different germ layers. For example, absorption of miRNA‐A by an ICM cell could suppress the endoderm and ectoderm lineage in that particular cell and thus facilitate mesoderm commitment. Similarly, the absorption of miRNA‐B by an ICM cell could suppress the mesoderm and ectoderm lineage in that respective cell and could direct the cell towards the endoderm lineage; the absorption of miRNA‐C by an ICM cell might facilitate ectoderm commitment by suppressing the mesoderm and endoderm lineages. Muc1, mucin 1, cell surface associated; c‐Myc, MYC proto‐oncogene, BHLH transcription factor; TGFβ, transforming growth factor beta; Reck, reversion inducing cysteine‐rich protein with kazal motifs; Mmp9, matrix metallopeptidase 9; Pten, phosphatase and tensin homolog; Ptgs2, prostaglandin‐endoperoxide synthase 2; Zeb1, zinc finger E‐box binding homeobox 1; Zeb2, zinc finger E‐box binding homeobox 2; Tiam1, T‐cell lymphoma invasion and metastasis 1; Rac1, Rac family small GTPase 1; Igf1, insulin like growth factor 1; Igf1r, insulin like growth factor 1 receptor; Oct4, octamer‐binding protein 4; Nanog, nanog homeobox; Klf4, kruppel like factor 4; Smad5, SMAD family member 5; Id2, inhibitor of DNA binding 2; Lefty2, left–right determination factor 2; Acvr1b, activin A receptor type 1B; Smad2, SMAD family member 2; Hdac, histone deacetylase; TIMM8A, translocase of inner mitochondrial membrane 8A; EED, embryonic ectoderm development; SMAD4, SMAD family member 4.