Role of miRNAs in the development and implantation of embryo.
Abstract
This book chapter will provide an overview of the functional role of microRNAs (miRNAs) in embryogenesis. A brief introduction to embryogenesis and emphasis on the importance of miRNAs in gene regulation will be provided. The biogenesis and mechanism of action of miRNAs will be discussed in detail with a focus on the importance of miRNA-mRNA interaction in gene regulation. The chapter will then delve into the role of miRNAs in early embryonic development, including their importance in the establishment of the three germ layers, cell proliferation, differentiation, and apoptosis during embryogenesis. The role of miRNAs in organogenesis and tissue differentiation, specifically the formation of specific organs such as the heart, lung, liver, and brain, will also be discussed. The chapter will conclude by examining the dysregulation of miRNAs in embryonic development and disease, including teratogenicity, developmental disorders, and developmental cancer. The chapter will summarize the functional roles of miRNAs in embryogenesis and will offer future perspectives and potential therapeutic applications of miRNAs in embryonic development and disease.
Keywords
- miRNAs
- embryogenesis
- gene regulation
- organogenesis
- development
1. Introduction
Small noncoding RNAs, also called miRNAs, which have a length of about 22 nucleotides, control the expression of genes at the posttranscriptional stage by selecting mRNAs for cleavage or transcriptional repression [1]. The majority of embryonic alterations can be connected to the genome’s activity [2]. According to mouse studies, genomic data within preimplantation embryos undergoes wave-like alterations related with maternal transcriptome disintegration and zygote genome activation (ZGA) [3]. Despite the fact that miRNA regulates transcription, it is still unclear how it affects the removal of the maternal genome. According to studies, mouse oocytes and early preimplantation embryos exhibit usually decreased miRNA function [4]. The timing of extensive maternal gene breakdown is consistent with the inhibition of miRNA activity occurring before the two-cell stage. The expression of miRNA is revived, and the repression is lifted after the two-cell stage [5]. miRNA is short RNA molecules that regulate the translation and transcription. The formation of miRNA is done by folding of small hairpin structure by the transcription of RNA polymerase II translation repression, and mRNA degradation is brought on by the synthesis of miRNAs in the nucleus as primary (pri)-miRNA and pre-miRNA, mature miRNA duplexes, RNA-induced silencing complex (RISC) strand-mediated complex, and complementary mRNA sequence synthesis (in the cytoplasm). Before implantation, a fertilized egg undergoes continuous cleavage to create an implantable embryo in a process known as embryogenesis. There are several factors, which characterize embryonic development, including the breakdown of maternal stores, activation of minor and major embryonic genomes, breaking down of the embryo and developing the embryonic cavity, and proliferation of embryonic cells into the inner cell mass and the outer epithelial trophectoderm [6]. The importance of stage-specific miRNAs throughout the early stages of mammalian embryogenesis is recognized, as is the involvement of coding genes. The first indication of the significance of micro RNAs (miRNAs) in embryonic development was acquired after the ablation of miRNA-treating genes such as Dicer, which is a key player in the start of RNA silencing because it recognizes double-stranded RNAs (dsRNAs) and uses its RNase III-like double-stranded RNA-specific nuclease activity to cleave them into short RNAs and Argonaute RISC Catalytic Component 2 (AGO2), which is a gene that codes for proteins. AGO2 serves a variety of roles, including RNA interference, translation repression, and heterochromatinization, which are all significant in small RNA-guided gene silencing processes [7, 8]. This resulted in an embryonic stop at E6.5 or embryonic mortality at gastrulation. In order to control the quantity or concentration of proteins or enzymes, miRNAs can either degrade mRNA or prevent protein translation. This can either promote or impede embryonic growth. The importance of miRNA before implantation, embryo growth between maternal zygote change, compaction, and blastocyst development has been shown by specific functional investigations or miRNA profiling research. From the zygote and two-cell stage, there is significant breakdown of maternally derived miRNAs, and during mouse embryogenesis, a variety of miRNAs are produced entirely from scratch reduced amounts of intact and hatched blastocysts and elevated Let-7a expression up to the eight-cell stage. The activity of miR-205, miR-150, miR-96, miR-122, miR-146a, miR-145, miR-208, and 496 elevated after bovine minor or major embryonic genome activation. In the initial bovine blast, miR-135a, miR-218, miR-335, and miR-449b are increased [9, 10, 11, 12].
These critical developmental processes, such as embryonic cell segregation, embryonic outgrowth growth, and later implantation, are thought to be regulated by miRNA. Throughout these critical stages of embryo development, miRNA dysregulation may have an impact on cell differentiation and subsequent embryo implantation. In this context, Dicer knockout testing revealed that miRNA may retain trophoblast stemness by lowering the activity of Cdkn1a (p21) and Cdkn1c (p57) genes, as well as epiblast pluripotency by avoiding apoptosis. Furthermore, previous research found miRNA in both first trimester and term trophoblast cells, but different miRNAs were expressed in each of these cells, demonstrating that miRNAs may show a part in different trophoblast cell characteristics. The restricted expression of miR-93 on the trophectoderm and upcoming embryonic endoderm, as well as enhanced expression of miR-106a in the inner cell mass, point to a potential involvement for these miRNAs in embryonic differentiation. Additionally, 526 miRNAs, including let-7b, miR-23a, miR-27a, miR-291a, miR-425, and miR-429, showed differential expression among embryos in blastocyst stage and those in embryonic outgrowth stage. Similarly, eight-cell stage embryos and trophoblast tissue have variable expression levels of certain miRNAs [12, 13, 14, 15, 16].
miRNAs regulate posttranscriptional gene expression as supported by the fact that around 30% of human genes can have their expression altered by miRNAs, which are distributed in tissue-specific patterns. miRNAs show a significant part in regulating gene expression. Understanding the molecular mechanisms that govern miRNAs is critical since they are frequently dysregulated in a number of human ailments, such as cancer and immunological disorders. RNA polymerase II generally generates major transcripts from miRNA-encoding genes, which are subsequently cut into short RNAs of roughly 21 nucleotides by RNase III endonucleases Drosha and Dicer. The RNA-induced silencing complex (RISC) functions as a posttranscriptional regulator by binding to the 3′-untranslated region (UTR) of mRNAs. It is essential for selecting the start codon and facilitating ribosome binding to the mRNA. Additionally, it significantly influences translational efficiency regulation and the development of the cellular proteome [17], encompassing all miRNAs. This seed-dependent miRNA binding inhibits the translation of its mRNA targets and/or promotes their splicing into nonfunctional forms [18, 19, 20, 21, 22]. Unexpectedly, current work provides proof of a target-mediated decay mechanism that regulates the concentration of certain miRNAs. Unexpected miRNA activities have also been found, together with a variety of noncanonical genes harboring miRNA. For instance, some miRNAs work in the nucleus to activate or silence target genes during transcription. These epigenetic alterations are attracted to particular genomic loci by RISC which participates in the breakdown of target mRNA, lowering the amount of transcript accessible for ribosome translation and directed there by miRNAs [23] as shown in Figure 1.
2. miRNAs biogenesis and mechanism of action
The process of creating miRNAs begins with DNA sequences known as miRNA genes, or with gene clusters that are only transcripted as miRNA molecules or collectively as polycistronic transcripts, correspondingly. A protein-coding gene’s intron or non-translated region (UTR) may also be where miRNAs are found. The canonical and noncanonical versions of the two primary biogenesis routes were determined [24].
2.1 Canonical miRNA biogenesis and functions
By use of RNA polymerase II, miRNAs are produced as primary transcripts. Drosha and its cofactor DGCR8 recognize and cleave one or more stem loops that are present in pri-miRNAs. Exportin 5 is a Ran-GTP-dependent mechanism that exports the resultant pre-miRNA from the nucleus. A mature miRNA duplex with two strands that are each 21–22 nt long is produced in the cytoplasm by the processing of the pre-miRNA by Dicer and its cofactor TRBP. After that, the RNA-induced silencing complex (RISC) incorporates this miRNA duplex [25].
To initiate miRNA production, primary miRNA transcripts (pri-miRNAs) from the genome are processed post- or co-transcriptionally. Conventional pri-miRNAs, which are normally transcribed due to RNA polymerase II (POL II), have a 5′-cap, and include one, do not necessarily have a poly-A tail [26].
The majority of mature miRNA genes can express themselves singly or in groups and are found in functional gene coding or noncoding areas. Drosha and Dicer, two RNase III enzymes that catalyze two additional processing stages in the nucleus and cytoplasm, are responsible for the synthesis of miRNAs [27, 28]. In the nucleus, genomic DNA is translated into a long primary miRNA (pri-miRNA). Drosha then cleaves this miRNA to produce a precursor miRNA (pre-miRNA) with a hairpin structure and a length of around 70 nucleotides (nt). These hairpin RNAs are moved nuclear leakage enters the cytoplasm receptor exportin-5, where Dicer cleaves them into mature miRNAs of 19–23 nt active miRNAs can also be produced
The microprocessor complex is a protein complex, which involves in the initial steps of processing for microRNA (miRNA) and RNA interference (RNAi) in animal cells [30]. The complex, which converts main miRNA substrates to pre-miRNA in the cell nucleus, is made up mostly of the ribonuclease protein Drosha and the dimeric RNA-binding proteins DGCR8 (also called Pasha in nonhuman species) [31]. Microprocessor also comprises of two units of multiple proteins, transcribes primary miRNAs (pri-miRNAs) from their genes, and then processes them into precursor miRNAs (pre-miRNAs). Introns and noncoding RNA genes are both potential sources of pri-miRNA substrates. In the latter scenario, there is evidence that the spliceosome and microprocessor complex interact and that pri-miRNA processing takes place before splicing [32]. Its two components have been found to be both necessary and sufficient to mediate the formation of miRNAs from pri-miRNAs [30]. One of them is a massive multiprotein complex made up of multiple RNA-associated proteins, ribonucleoproteins, dsRNA-binding proteins, and the family of Ewing’s sarcoma proteins. The other is Drosha, tiny multiprotein complex that contains the enzyme RNase III, as well as the DiGeorge syndrome critical region 8 RNA protein complex (DGCR8). The microcontroller identifies certain pri-miRNA patterns and splits it at the bottom of the distinctive hairpin form, resulting in a pre-miRNA, there is a 3′–2–nt overhang and a 5′–monophosphate. Afterward, a complex of exportin5 (XPO5) and the nuclear protein guanosine-5’-triphosphate-ase, which is connected to RAS, was formed (Ran-GTPase). This complex exports pre-miRNAs from the nucleus to the cytoplasm. The RNase III endonuclease Dicer eliminates the terminal loop of pre-miRNA in the cytoplasm [33, 34]. miRNAs are currently loaded, entering the complex for RNA-induced silencing (RISC) as short RNA duplexes called miRNA duplexes [34, 35].
2.2 NonCanonical miRNAs
There are miRNAs known as noncanonical miRNAs that are produced using a distinct biogenesis mechanism. Recently, different miRNA biogenesis routes have been identified. Certain noncanonical pri-miRNAs, for example, are known as mirtrons and are stored in coding genes’ introns [23]. Like typical introns, all mirtrons undergo initial processing by the nuclear splicing machinery before creating sturdy, stem-less hairpins than canonical pri-miRNAs. Only one annotated miRNA has been found to process independently of DICER so far. Pre-miR-451 miRNA maturation necessitates the AGO2 slicer activity because of its stem-loop shape is too shorter for DICER to cleave [23]. Pre-miR-451 processing by AGO2-mediated processes and eventual RISC loading are influenced by the length of the stem-loop structure, inappropriate base pairing in the stem, and low GC content in the distal stem, among other factors. Furthermore, miR-451 processing by AGO2 is dependent on the function of eukaryotic translation initiation factor 1A, another RISC component (EIF1A) [23].
It has been predicted that mirtron formation occurs during noncanonical miRNA biogenesis. RNA Pol II transcribes mirtrons as introns of protein-coding genes. These mirtrons are spliced by the spliceosome, debranched, and (if necessary) exosomal trimmed. Mirtrons are considered as canonical miRNAs after undergoing these preliminary processing stages, and Exp5 then transports them to the cytoplasm, where they are processed by Dicer and TRBP and then integrated into the RISC. Also, it has been highlighted the production of miRNAs independent of Dicer. RNA Pol II produces the Dicer-independent miRNA miR-451, which is then processed by Drosha/DGCR8 and exported from the nucleus by Exp5. Argonaute 2 (Ago 2) binds to miR-451; once it is inside the cytoplasm, where it is then cut into the functional, mature, single-stranded miRNA [25].
2.3 shRNA- snoRNA- and tRNA-derived miRNAs
The family of ncRNAs known as snoRNAs, which range in length from 60 to 300 nt, is typically found in cells’ nucleolus, where they may alter tRNAs rRNAs and snRNAs. Through the H/ACA box on their rRNA precursors, snoRNAs can control the methylation and pseudouridylation of specific rRNA sites. According to a number of lines of evidence, certain snoRNAs can serve as the building blocks for noncanonical miRNAs. These noncanonical miRNAs are produced by use of a biological process, which resembles the synthesis of canonical miRNAs in that it involves the Dicer, Dgcr8, and AGO enzymes. Dicer and Dgcr8 are required for the stabilization and degradation of the purportedly derives from snoRNA miRNAs [36]. SnoRNA-derived miRNAs are 21 nt long, equivalent to miRNAs, and can link to AGO enzymes such as AGO1 and AGO4 to inhibit mRNA targeting [36, 37]. Contrarily, the production of two snoRNA-derived miRNAs called ACA45 and GlsR17 shows a dependence on Drosha/Dgcr8 rather than Dicer [36, 37]. The unusual precursor structure of these snoRNA-derived miRNAs consists of two hairpins resembling pre-miRNA connected
tRNA-derived miRNAs are created through tRNA development, although they have activities comparable to miRNAs, such as RNA transcript suppression. However, compared to traditional miRNAs, their affinity for Ago proteins appears to be less., which is probably because of their susceptibility to posttranscriptional modifications. Although little is known about their function, tRNA-derived miRNAs may support cell growth and miRNA biogenesis [37, 38, 39, 40].
Exportin 5 transports a pre-miRNA hairpin enters the cytoplasm and forms a miRNA duplex is formed following a Dicer’s second cycle of endo nucleolytic cleavage [41]. Certain miRNAs are processed by Dicer a few organisms through interactions with supplementary RNA-binding proteins such as loquacious and TRBP. [42]. These RNA-binding proteins’ posttranslational modifications can influence Dicer activity and the biogenesis of specific miRNAs [29]. Following duplex unwinding and strand selection, the mature miRNA is loaded into the Argonaute protein, which the miRNA-induced suppressing complex’s core component (miRISC) [41]. Through sequence complementarity, the targeting mRNAs’ 3’UTRs are bound by the miRISC-associated miRNA, which also attracts downstream effectors and typically causes translational suppression and mRNA degradation [43]. The seed sequence is the first 2–8 nucleotides from the mature miRNA’s 5′ end. To pair with a target mRNA, the seed sequence must be nearly full, while exhibiting partial symmetry along the remainder of the miRNA and the target. MiRNAs that have the identical seed pattern are members with the same family of miRNAs. A plethora of computational and biological approaches have been developed to anticipate and confirm miRNA-mRNA target pairings [44].
Argonaute posttranslational changes can influence steady-state miRNA activity [45]. The orthologs of Argonaute in humans and
3. miRNAs in early embryonic development
3.1 The role of miRNAs in preimplantation development
The free-living stage of mammalian development from the one-cell zygote to blastocyst adhesion or implantation into the uterine wall is known as preimplantation development. The first week of development is typically covered by it, and key moments such the change from parental to embryonic genomic activation (EGA), compaction, and cavitation or blastocyst formation are included [51]. The primary result of preimplantation development is the creation of an embryo that is implantation-competent for the start of pregnancy. To achieve this, the trophectoderm (TE), which develops into the blastocyst’s outer layer and connects with the endometrium to start implantation, must first take shape. The embryonic element of the placenta is likewise derived from the TE. The initial stage of the embryo proper is the inner cell mass (ICM), a second cell type that is still pluripotent. These cells continue to be contained within the polar and mural TE of the blastocyst. Therefore, TE differentiation rather than embryogenesis is the focus of preimplantation development as placental mammals must first meet this criterion for implantation and placental growth before embryogenesis can occur [51].
The animal embryo moves between the oviduct and the uterus after fertilization. The embryo then implants, forming a link with maternal tissues as depicted in Figure 2. Embryonic development in mammals a diploid zygote is created when a sperm and an egg are united. The zygote proceeds through a sequence of cleavage divisions that increase the number of blastomere-containing cells while maintaining the embryo’s total volume. Following cleavage, the eutherian embryo goes through compaction, in which the compaction of the embryo one another to form a tight ball of cells known as a morula [52].
miRNAs, which are around 22 nucleotides long, provide guidance molecules in the RNA silencing process. MiRNAs have a role in nearly every animal developmental and pathological process, targeting the majority of protein-coding transcripts [53]. A crucial step is embryo implantation. In the creation of a pregnancy in animals and happens over a “period of implantation” is a certain time frame [54]. Apposition, attachment, and invasion are the three stages of implantation [55]. The receptive endometrium, which is produced by widespread endothelial edema on the surface of the inner uterus, interlaces with the microvilli of the cytotrophoblast on the outer surface during apposition [56]. Furthermore, the receptive endometrium expresses heparin-binding growth factor similar to EGF (HB-EGF), and cells expressing Blastocysts are adhered to by transmembrane HB-EGF with ErbB4 on their cell surface [57]. Activated blastocysts increase the expression of HB-EGF, which causes its own expression of genes at the blastocyst apposition location in the endometrium
During the preimplantation stage of development, the embryo secretes extracellular miRNAs are introduced. MiRNAs are secreted into biological fluids in the extracellular setting by a variety of cell types. These miRNAs generated from fluid have been demonstrated to circulate in the body. The appropriate packing of vesicles that contain miRNAs outside of cells, especially exosomes, is required for stable transport. At the forefront of studies into cell-to-cell communication are these vesicles, which transport RNA, DNA, and proteins. The presence of EVs in their miRNA content was found in uterine fluid. Their miRNA content was found in uterine fluid, which is expected to facilitate interaction between the mother and conceptus. Uterine fluid is one of the reproductive fluids where they have been discovered (Table 1) [61].
miRNAs | Function | References |
---|---|---|
miR-143 | Proliferating, migrating, and invading cells of human endometrial stroma | [62] |
miR-193 | In the uterus of mice, implantation rate is controlled. | [63] |
miR-181 | Control of the implantation rate in the mouse uterus | [64] |
miR-29b | Development of a calf using somatic cell nuclear transfer (SCNT) | [65] |
miR-126a-3p | Development utilizing nuclear somatic cell sojourning in bovine embryos (SCNT) | [66] |
miR-200a | Counting the implantation spots in the rat endometrium | [67] |
3.2 The importance of miRNAs in the establishment of the three germ layers
A large a group of noncoding RNAs known as miRNAs function as RNA silencing guide molecules and are approximately 22 nucleotides long. Animal processes, both developmental and degenerative virtually, universally involve miRNAs, which primarily target protein-coding transcripts [53]. The “window of implantation” refers to the constrained time period during which embryo implantation, an essential step in the creation of pregnancy in mammals, takes place (WOI) [54]. Apposition, attachment, and invasion are the three stages of implantation [55]. The receptive endometrium, which is produced by widespread an inner uterine surface with stromal edema, interlaces with the microvilli of the cytotrophoblast on the outer surface during apposition [56]. Additionally, the receptive endometrium expresses heparin-binding growth hormone similar to EGF (HB-EGF), the ErbB4-expressing cells that participate in this adhesion to blastocysts [57], and the ErbB4-expressing cells that participate in this adhesion to blastocysts
The uterine surface in order to secure the embryo into biological fluids in the extracellular environment by a variety of cell types. These miRNAs generated from fluid have been demonstrated to circulate in the body. The appropriate packing of extracellular vesicles containing miRNAs (EVs), especially exosomes, is required for stable transport. The study of cell-to-cell communication is currently focused on these vesicles, which transport RNA, DNA, and proteins. EVs have been discovered in a number of reproductive fluids, such as uterine fluid, where it is believed that their miRNA content serves as a mechanism for mother and child chit-chatting conceptus [61].
3.3 The role of miRNAs in cell proliferation, differentiation, and apoptosis during embryogenesis
MiRNAs have a significant impact on a variety of cellular processes, such as differentiation and proliferation, that are regulated by intracellular signaling. Major examples of these signaling cascades are the nuclear factor kappa-light chain-enhancer of activated B cells (NFkB), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinases (PI3K), notch, transforming growth factor (TGF), and hedgehog (Hh) pathways. MicroRNAs may regulate cell signaling by suppressing the expression of their target genes, which produce molecules involved in these important signaling pathways [69, 70]. Additionally, a number of signaling mechanisms control miRNA expression. For instance, in rat vascular smooth muscle cells (VSMC), an active MAPK pathway increases miR-31 expression. In PC12 cells, a rat pheochromocytoma cell line of the adrenal medulla, the nerve growth factor (NGF) increases expression of miR221, miR-222, with NGF induction itself dependent upon activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathways [71]. In signaling cascades, microRNAs may potentially establish regulatory feedback loops. In many physiological processes, there are several regulatory loops between miRNAs and their targets. In THP-1 cells, a cell line for human acute monocytic leukemia, a regulatory loop between miR-146 and NF-B has been identified [72]. Through mediating inter-pathway crosstalk, microRNAs may operate as a connecting agent between several signaling pathways [70, 73]. For instance, in the early stages of embryonic patterning, miR-15 and miR-16 link the Wnt and TGF- signaling pathways. To sum up, miRNAs play a role in controlling intracellular signaling pathways. Additionally, they create intricate links between various signaling pathways. Changes in intracellular pathways are linked to a number of diseases in humans.
Preimplantation embryos from mice and humans can produce the placenta, yolk sac, and the three germ layers of the fetus, respectively, through the actions of the epiblast (EPI), primitive endoderm (PrE), and trophectoderm (TE) [74]. Years of work have resulted ESCs, XEN (extraembryonic endoderm) stem cells, and trophoblast stem cells are three
MiRNAs can influence adult stem cell destiny in a variety of ways; a type of stem cell called epiblast (EpiSC), and hematopoietic stem cells (HSCs) hinders whereas miR-16, miR-103, and miR-107 expression decrease proliferation, and they promote differentiation [78]. MiRNAs have been shown to influence a variety of differentiation processes such as myogenesis, cardiogenesis, neurogenesis, and osteogenesis [79].
miRNAs linked with stem cell development are expressed is regulated at several levels, for instance, posttranscriptional, epigenetic, and/or transcriptional control; cluster of miR-362 and miR-367, for instance, is regulated by transcription factors (TFs) connected to the ESC, including Oct3/4, Sox2, and Rex1 [80], which promote the self-renewal or generation of pluripotent stem cells. Studies on the transcriptional control of miRNA production in ESCs have shown, which bicistronic or monocistronic miRNAs at intergenic loci are regulated by shared upstream transcription regulators, bicistronic or monocistronic in nature. Along with the bi-cistronic miRNAs mir-1 and mir-133, mir-206, mir-486, and mir-499, are induced by MyoD, Myogenin, and MYF5 during human muscle stem cell (hMSC) growth [81]. It is interesting to note that the co-regulated miRNAs mir-1 and mir-206 in various Chromosomes share a seed sequence with members of the same miRNA family that downregulates relevant targets [82].
Cells that would typically be harmful to the organism’s survival are eliminated during apoptosis, a sort of active, and cell-autonomous caused cell death. The so-called intrinsic pathway, which includes mitochondria and stressors, can start this death response. Alternatively, the extrinsic system, which involves a cognate ligand, might start it by activating death receptors on the cell membrane [83]. In 2003, the first papers on the regulatory functions of miRNAs in apoptosis were published. Through the inhibition of the effector caspase Dicer and the proapoptotic high temperature-induced Dauer synthesis family member (hid1) genes, respectively; it was demonstrated in these Drosophila research that miR-14 and bantam govern cell death. Since then, both intrinsic and extrinsic routes have been revealed to contain many miRNA families that regulate apoptosis. The discovered miRNAs have possibly pro- or antiapoptotic characteristics [84].
Extrinsic signaling pathways are occupied by a large number of miRNAs. miR-7 specifically sensitizes cells from hepatocellular cancer and glioblastoma multiforme to TRAIL-mediated apoptosis [85]. In human acute myelogenous leukemia cells to improve cell survival, miR-590 targets Fas ligand (FasL) and is regulated utilizing the STAT5 (Signal Transducer and Activator of Transcription) pathway [86]. MiR-21, a direct FasL target in pancreatic cancer, prevents cancer cells from dying from gemcitabine-induced apoptosis when it is expressed ectopically [87]. Fas expression in osteosarcoma cells is decreased by miR-20a, promoting tumor cell proliferation, and metastatic potential [88]. Additionally, miR-146a and miR-196b prevent the expression of Fas, and leukemia is brought on by ectopic miR-196b expression [89]. The expression of Fas is also inhibited by miR-146a and miR-196b, and leukemia is caused by ectopic miR-196b expression [89]. miR-25, which is associated with intrahepatic bile duct. It is more common for malignancy to directly target DR4 and resist TRAIL-mediated apoptosis [80]. There is an increase in malignancy, which has been demonstrated to directly target DR4 and shield against TRAIL-mediated apoptosis. Although miR-128a antagonists increase Fas-mediated apoptosis, ectopic miR-128a In Jurkat cells, expression raises Fas resistance by targeting FADD [90]. By inhibiting the expression of miRNA-186*, which targets the caspase-10 enzyme, which is identical to caspase-8, curcumin induces death in A549 cells [91]. MiR-708 improves the susceptibility a kidney cancer cells multiple apoptotic stimuli and adversely controls the expression of c-FLIP [19]. Three miRNAs, miR-378, miR-155, and miR-let-7a, target caspase-3 that can regulate the apoptosis of cancer cells [92]. Specifically targeting caspase-7, miR-106b is linked to the prostate cancer coming back [93]. For the purpose of controlling pancreatic cancer cells undergo apoptosis,miR-133 and miR-24a directly inhibit caspase-9 [94].
A variety of miRNAs are also involved in the regulation of the apoptotic regulator genes in the intrinsic route for apoptosis. It has been demonstrated that miR-365 specifically targets the protein adaptor Src homology 2-containing subtype 1and the Bcl-2-like protein 4 (Bax) (SHC1)in lung adenocarcinoma and lung cancer cell lines [95]. In gastric cancer cells, miR-125b expression is markedly downregulated. Overexpressing miR-125b, however, prevents stomach cancer cell lines from proliferating, migrating, and invading (HGC-27 and MGC-803) (95)miR-148a and miR-204 cause apoptosis
miRNA | Function | References |
---|---|---|
miR-21-3p | Inhibits the cow granulosa cells undergo autophagy | [100] |
miR-383 | Prevents autophagy in granulosa cells of cattle | [101] |
miR-183-96-182 cluster | Controls apoptosis in the granulosa cells of the porcine ovary | [102] |
miR-1275 | Involved in the synthesis of estradiol and death in porcine granulosa cells | [103] |
miR-92a | Controls the apoptosis of granulosa cells in porcine ovary | [104] |
miR-15a | Controls the granulosa cells in the human ovary produce steroid hormones and promote cell growth | [105] |
miR-96 | Controls the growth of cells and the synthesis of steroid hormones in human ovarian granulosa cells | [106] |
miR-126-3p | Encouraging in porcine granulosa cells, cell growth, and averting cell death | [107] |
miR-181a | Control oxidative stress-related acylation of the fork head box protein O1 (FOXO1) and mouse granulosa cell apoptosis | [108] |
miR-23a. miR-27a | Granulosa cells in humans undergo apoptosis | [109] |
miR-99a | Polycystic ovarian syndrome (PCOS) sufferers’ granulosa cell growth and death are controlled. | [110] |
miR-335-5p | In women with polycystic ovarian syndrome (PCOS), the regulation of granulosa cell growth and apoptosis is in place. | [111] |
miR-125b | Controls the apoptosis of the yak ovary’s granulosa cells | [112] |
miR-143 | Encourages human granulosa cell proliferation and estradiol synthesis that is produced by follicle-stimulating hormone (FSH) | [113] |
4. miRNAs in organogenesis
4.1 The role of miRNAs in organogenesis and tissue differentiation
miRNAs may be crucial for differentiation and organogenesis in
This conditional-knockout research in mice has a special warning because it is frequently difficult to determine how effectively any and the Dicer preexisting When Dicer1 is deleted somatically, miRNA pools are depleted. In reality, miRNAs do seem to last a while [116]. One particular miRNA, MiR-181, has been directly associated to the maturation of B cells [118]. This miRNA is highly expressed in mouse B-lymphoid cells. Hematopoietic stem cells overexpress some genes and increases the proportion of B-lineage cells both
The Dicer1 knockdown in
5. The importance of miRNAs in the formation of specific organs
5.1 Heart
Each of the several stages of development involves a number of substances with inducing or suppressing capabilities [122].
Preliminary cardiac precursor cells have been found in the mouse and chick embryo’s front portion of the primitive streak, according to tracing investigations using studies using cell/tissue explants and essential dyes [123]. The FGF family of molecules’ action signaling molecules, which includes the FGFs FGF2, FGF4, and FGF8 have been postulated to indicator through FGFR1, controls the initial movement of these cells from the posterior to the anterior at the start of gastrulation [124, 125]. Similar to TGF-, bone-forming protein 2 (BMP2), a growth factor belonging to the TGF- superfamily, is first expressed toward the final phase of the primitive phase by the start of gastrulation and is associated with early cell migrations [126].
As a result of Mesp-1 and Mesp-2 being expressed in an FGF-8-dependent manner at embryonic day 6.5 (E6.5); Bilaterally, cardiac progenitor cells move to the front and side of the heart of the embryo, colonizing the lateral plate mesoderm splanchnic layer, and forming two early lateral cardiac fields [127]. Mesp-1 positive mesodermal lineage is induced by canonical Wnt/−catenin signaling in the neural ectoderm during early gastrulation [128]. These findings support significant roles for early Bmp2 and FGF signaling in establishing cardiogenic potential [129], limiting the position of the cardiac fields, and directing progenitor cell movement. By acting as a concentration gradient of Wnt/−catenin, the underneath anterior mesoderm can be induced into head tissue [130].
A day later (E7.5), the cardiac crescent, a horseshoe-shaped epithelial fold, is formed when these earliest cardiogenic stem cells travel cranially and congregate across the midline region of the embryo. Nkx2-5, a vertebrate homeodomain transcription factor and
At E9.5, the cardiac tube is bent to the right to adjust the heart’s chambers (looping), and the caudal region of the cardiac tube is brought cranially to position the two sinus venosus horns dorsally to the outflow tract. Since the sinus venosus moved the right side of the heart by E10.5, the cardiac looping process is almost finished. The right atrium and common cardinal vein on the right are joined at this point, which is indicated by the emergence of two outgrowing structures known as the sinus valves. Additionally, at E10.5, the cardiac chambers have begun to septate [139, 140]. By E11.5, the heart’s caudal region is at last dorsal to the arterial pole, and in oxygen-breathing vertebrate species, the heart chambers will then become septate is the last step in their specification. The outflow route is initially divided into an arterial and pulmonary arch by the creation of internal cushions. The left horn shrinks and changes into the coronary artery as the right sinus venosus horn is placed in close proximity to the right atrium. The interatrial and interventricular septa, respectively, divide the atria and ventricles [125, 141].
5.2 Lung
Similar divisions between the stages of lung development in mice and humans, including canalicular, terminal saccular, and pseudoglandular, and the final alveolar stage, are present in both species [142]. Total miRNA levels in the mouse embryo at the two-cell stage were found to be considerably lower than those in the one-cell zygote following fertilization [9]. A noteworthy difference between the two-cell stage and the four-cell stage embryos was the overall miRNA levels [9]. Inhibiting sections of cultured tissue from mouse lung E12 smoothened led to an increase in the distal epithelial size, as well as to disturb the usual branching pattern and mesenchymal integrity [143]. Inhibiting smoothened in cultured explanted E12 mouse lung caused distal epithelium to enlarge and disrupted the mesenchymal integrity and normal branching pattern. Mesenchymal progenitors’ growth and differentiation in the lung development of mice were controlled by miR-142-3p after it was all said and done [144].
The amount in the forming mouse lung miR-17 was steady from E11.5 to E16.5; it was mostly present at the pseudoglandular stage, with greater epithelial levels around E12.5 [145]. MiR-17 levels in the developing mouse lung were steady (E11.5–E16.5), primarily when pseudoglandular with greater epithelial levels at E12.5 [145]. In the rat embryonic lung, miR-449a levels increased from E15.5 to E18.5, and miR-449a was upregulated in the human fetal lung at 18–20 weeks (canalicular stage) [146]. Levels of Mycn and Sox9 mRNA and SOX9 and Ki-67protein were all elevated at the distal end of the epithelium of E16.5 mouse lung culture when miR-449a was inhibited (end of pseudoglandular stage) [146].
The deletion of miR-26a-1 and miR-26a-2 in mice enhanced the creation of dilated lumens and aerated patches at the beginning of the neovascularization stage (E16.5 of lung development) [147]. The miR-26a mutant mice’s results at the level of secularity (E18.5) likewise showed enlarged crystalline bodies and higher amounts of the proteins SP-A, SP-B, and SP-C. The findings also suggested that miR-26a is implicated in the pulmonary surfactant generation [147]. MiR-17-92 cluster and miRNAs in the Dlk1–Dio3 locus were upregulated in the E18.5 mouse lung after epithelial histone deacetylase 3 was lost [148]. Embryonic mouse lung epithelium overexpressing miR-17-92 indicated densely packed AT1 cells. The results of the study collectively demonstrated that histone deacetylase 3 controlled miR-17-92 levels, which, in turn, affected TGF- signaling and, ultimately, AT1 cell spreading and saccular formation [148]. The highest amount of miR-127 was found in the fetal rat lung at E21 [149]. Additionally, the size of the terminal and internal buds was increased by overexpressing miR-127 in fetal rat lung (E14) culture.
In research on alveolarization, bronchopulmonary dysplasia (BPD) mouse models have been used. After, the treatment of miR-876-3p mimics repaired alveolar architecture and reduced neutrophilic irritation in postnatal day 14 animals that had been subjected to hyperoxia [150]. After exposure to hyperoxia, levels of miR-30a-3p and -5p were significantly increased in the lungs of female mice on postnatal days 7 and 21 [151]. In total, significant reductions in miR-30a-3p and -5p levels were observed, whereas DLL4 mRNA and protein levels were elevated in human BPD lung samples [151].
5.3 Brain
A KO would be very difficult because of the 12 different members of the miRNA Let-7 family, which is strongly expressed in the brain. In addition, miRNAs are frequently transcribed in groups. Therefore, the manifestation of a different unrelated miRNA in the same cluster may be affected if one miRNA gene is deleted or otherwise altered. Along with having overlapping targets, miRNA families also have the same seed sequence. It follows that other family members would probably make up for the loss an individual’s family. Even with these challenges, reports of miRNA knockout (KO) mice have allowed for loss-of-function studies for particular During developing brain, miRNAs [151].
One of the most abundantly produced miRNAs in the mouse brain is miR-124, which is also highly conserved among mammals. When neural stem cells differentiate into neurons, miR-124 expression rises and is neural-specific [152, 153]. Reduced neurogenesis and a shift to gliogenesis are caused by neural stem cells permanently losing the ability to function as miR-124 [154]. MiR-124 is a neuronal destiny determinant, as determined by the forced neural differentiation that occurs when it is overexpressed in glioma cells, embryonic stem cells, HeLa cells, and neural progenitor cells [154, 155, 156, 157]. Three distinct loci for the miRNAs mIR-124-1, mIR-124-2, and mIR-124-3 yield the same mature sequence and are used to transcribe miR-124. Retinal noncoding RNA gene 3 has an exon from which the miR-124-1 stem-loop is translated (Rncr3). The nuclear localization, consensus sequence, and high amounts of miR-124 expression in the brain are all due to this gene, which also serves as its main source. In order to study the function of miR-124-1 during brain development, Rncr3 was deleted to create miR-124-1 knockout (KO) mice. In this work, it was discovered indicated there was a decrease in miR-124 expression by 60–80% in KO mice. Around postnatal day 20, the majority (60%) of KO mice perished. In addition to a large loss of cone cells and cell apoptosis in the cortex and hippocampus, Rncr3 KO mice also had smaller brains. Axons in the dentate gyrus of animals lacking Rnc3 also showed aberrant outgrowth. The tail suspension assay results in KO mice clasping their front and back limbs further demonstrated severe neuronal injury. Additionally, mouse models that mimic neurodegenerative diseases show this neuronal impairment. In conclusion, the KO of Rncr3 suggests that miR124 plays a significant role in murine brain development [158].
6. Dysregulation of miRNAs in embryonic development and disease
miRNAs have a role in differentially implantation and non-implantation of embryos; proliferative endometrium within women who face failed implantation and are used as a biomarker for embryo implantation [159], blastocyst development, and morula to blastocyst transition [160]; in short, they are involved in gametogenesis, embryogenesis, and mammalian fertility [12]. The role of short noncoding RNAs in gene expression is found in fully developed oocytes [160], ovaries, testis, and follicular fluid. During gametogenesis, miRNA are involved in the division and differentiation of stem cell and cell proliferation [84, 161] proved by knockout of Dicer1 gene [162] and AGO2 [163]. miRNA is involved in follicular development [164] through the regulation of vitamins, methionine, lipids, and cysteine [165]. miRNA has its role in testis development [166] as it is evident by its presence in Sertoli cells [167] and proved by the Dicer and Drosha development [166]. miRNA-1285, miRNA-762, miRNA-638, miRNA-15a,miR-29b,miR-34b and miR-34c has its role in spermatogenesis [168]. miRNA are also found in body fluids such as serum, saliva, urine, and blood plasma in the form of exosome or apoptotic bodies with the playing role as lipid or protein carriers [169, 170].
6.1 The effects of miRNA dysregulation on embryonic development and disease
miRNA can has deregulatory functions by destroying the translation process of protein making from mRNA [171]. This dysregulation has negative effects on embryonic development through having impact on stem cell division, cell proliferation, and on early or late embryonic development [161]. These negative effects lead to deleterious diseases such as tumors and cancers at the embryonic stage [172]. A total of 156 mature miRNAs are involved in embryonic cancerous diseases out of which colon cancer is greater in number [173]. Most importantly, miR-290–295, miR-302–367, miR-17–92, and miR-106b–25 are the set of miRNAs that are the controlling centers of embryonic diseases. Recent researches has also shown the effect of miRNA on protein output [174]. miRNA-383 is involved in infertility of men, maturation arrest, hyperactive proliferation of germ cells, G1-phase arrest, suppression of proliferation, and induction of apoptosis, and this effect is increased by the downregulation of IRF1. As described earlier, Dicer1, along with miRNA, has significant role in spermatogenesis. The Dicer1 deletion in the testis leads to defective spermatogenesis and during proliferation arrested at early differentiation. Only miRNA-372 and 373 are seen in defective spermatogenesis. This all would happen during early spermatogenesis stages, which can result in germ cell death [175]. miRNA expression is seen during different embryonic stages in mammals and thus can act as a biomarker for the selection of embryos for successful
6.2 miRNAs in developmental cancer
Different types of these small noncoding miRNAs are involved in different types of cancers [172], such as miR-15a is involved in leukemia [172], miR-145 in colorectal cancer [183], miR-21 in breast cancer [184], and let-7 of miRNA in lung cancer [172]. These dysregulated miRNAs can be oncogenes or tumor suppressors [172]. miRNA 17–92 are highly expressed in cancerous tissues in humans [174]. Amplification overexpression and depletion of miRNA lead to cancer [185]. miRNA are seen in genome effected with cancer [169]. miRNA is highly stable during extreme conditions of temperature and environment [186, 187]; so, miRNA is used as a biomarker for cancer such as lung, prostate, and colorectal cancer [184, 187]. miRNA expression gives 60% surety of cancer by analyzing serum, while 100% specificity is based on the effectiveness of miRNA [9]. Mutations, deletions, amplifications, epigenetic silencing, and dysregulation of transcriptional factors in miRNA loci are various processes that contribute to changes in the miRNA genome leading to cancer. The dysregulated miRNA genes are managed by protein-coding oncogenes or tumor suppressor gene. The tumor suppressor miRNA genes are B cell leukemia, lymphoma 2, MYC, RAS, phosphatase and tensin homolog (PTEN), p27, p57, and tissue inhibitor of metalloproteinases 3 (TIMP3). The silencing of miRNA genes gives epigenetic alterations that result in the silencing of tumor-suppressing genes. For example, the deletion of miRNA-29 causes DNA methyltransferase overexpression and results in tumor suppressor-silenced gene. The dysregulated miRNA can be used as biomarker for anticancer therapies [188].
Early B-cell lymphoma stages have greater levels of miRNA-21 expression; miRNA-200 and miRNA-17 are functionally active in cancer. The alternated expressions of miRNA in cancer were first described and studied by Chalin et al. [189]. miRNA-34a expression is reduced in breast, colon, and lung cancer [190]. The miRNA-331 expression is reduced in nasopharyngeal carcinoma. MiRNA-21, miRNA-155, miRNA-17b, and miRNA-106b has oncogenesis roles in hematological malignancies, B-cell lymphoma, breast, lung, and metastatic breast cancer, respectively [191]. Limited oxygen supply and hypoxia regulate the function of miRNA [192]. Altered miRNA genomic expressions in cancer arise from genomic variation. For instance, B-cell chronic lymphocytic leukemia has a high frequency of deletions at the chromosomal locus of the miR-15/miR-16 cluster (CLL) [193]. For instance, B-cell chronic lymphocytic leukemia frequently has genomic deletions at the miR-15/miR-16 cluster locus (CLL) [194].
Introduction of single nucleotide polymorphism (SNP) into miRNA sequence itself results in miRNA dysregulation both in epigenetic and at genetic level that leads to breast cancer [195]. A total of 50% of miRNA genes are involved in deletion, amplification, and translocations implicated tumorigenesis [196]. In fact, it is observed that 755 of miRNA genome is involved in breast cancer-affected copy number variations [196]. miRNA silencing
7. Conclusion and prospects
MiRNAs control the physiological and developmental processes in a variety of animals, including embryos, by preventing the target genes’ translation or degrading their activity. Endogenous tiny noncoding RNAs, which range in size from prokaryotes to eukaryotes, play a significant role in the transcriptional and posttranscriptional control of many genes. They control the complicated gene expression connected to the intricate process of embryogenesis throughout embryonic development. Further, study is, therefore, necessary to understand how miRNAs regulate gene expression at the posttranscriptional level, especially given that they are the most significant posttranscriptional regulators recently identified.
miRNA is playing its role in cell differentiation, proliferation, apoptosis, tumorigenesis, developmental timing,
Proven by 24,000 peer-reviewed articles, miRNA has its role in cancer. miRNA is involved in breast cancer through non-targeting hyaluronic acid. The dysregulated miRNA is involved in the malignant phenotype of cancer cells. MiRNA has its role as a therapeutic agent. The combination of small anticancer drugs and miRNA is effective in the treatment of cancer. Reducing drug resistance, increasing apoptosis and autophagy, reducing tumor angiogenesis, and preventing the production of drug efflux are all ways to reverse the EMT are some of the useful advantages of miRNA therapies over the traditional convention ones. The use of targeted miRNA is also proved effective in therapies.
MiRNA is important in gametogenesis and spermatogenesis. During the preimplantation stage of development, the embryo releases miRNA in extracellular vesicle. miRNA is involved in oogenesis, spermatogenesis, and early embryogenesis. This also includes several proteins of miRNA, including Dicer, Drosha, and DiGeorge. Dicer1 has generalized functions in handling other short RNAs, particularly siRNAs; therefore, it is not exclusive to miRNAs. miRNA is also involved in abortion and infertility. It is seen that the expose of varies to external environment can bring changes in oogenesis in relation of miRNA. miRNA-regulated gene is important in normal spermatogenesis. The activity of miRNA changes in the testis with spermatogenesis development.
Acknowledgments
Authors are grateful to the Vice Chancellors of the University of Narowal, the University of Punjab, and the University of Okara for providing support to this study.
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