Molecular Development - microRNA

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Introduction

MicroRNA formation
MicroRNA formation[1]

Micro RNA (miRNA) are 22 nucleotide non-coding RNAs that regulate about 30% of mammalian genes.

The original "RNA family" consisted of just 3 main members; transfer RNA (tRNA), ribosomal RNA (rRNA) and messenger RNAs (mRNA).

These small pieces of RNA have been identified as important negative regulators in both development and adult cell processes involving gene expression. The repressive effects are typically relatively mild, with parallel regulatory mechanisms, the phenotype may require a stress condition or tissue injury for their expression.


miRNAs are initially transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature ~22 (20-24 nt) nucleotide miRNA and antisense miRNA star (miRNA*) products.

The miRNAs then bind (by imperfectly complementation) usually to 3′ untranslated region of target mRNAs, resulting in mRNA degradation and/or translational inhibition.


Molecular Links: molecular | genetics | epigenetics | mitosis | meiosis | X Inactivation | Signaling | Factors | Mouse Knockout | microRNA | Mechanisms | Developmental Enhancers | Protein | Genetic Abnormal | Category:Molecular

Some Recent Findings

Human CS13-15 otic vesicle.[2]
Bovine GIT miRNA expression[3]
  • Long and small noncoding RNAs during oocyte-to-embryo transition in mammals[4] "Oocyte-to-embryo transition is a process during which an oocyte ovulates, is fertilized, and becomes a developing embryo. It involves the first major genome reprogramming event in life of an organism where gene expression, which gave rise to a differentiated oocyte, is remodeled in order to establish totipotency in blastomeres of an early embryo. This remodeling involves replacement of maternal RNAs with zygotic RNAs through maternal RNA degradation and zygotic genome activation. This review is focused on expression and function of long noncoding RNAs (lncRNAs) and small RNAs during oocyte-to-embryo transition in mammals. LncRNAs are an assorted rapidly evolving collection of RNAs, which have no apparent protein-coding capacity. Their biogenesis is similar to mRNAs including transcriptional control and post-transcriptional processing. Diverse molecular and biological roles were assigned to lncRNAs although most of them probably did not acquire a detectable biological role. Since some lncRNAs serve as precursors for small noncoding regulatory RNAs in RNA silencing pathways, both types of noncoding RNA are reviewed together."
  • Developmental profiling of microRNAs in the human embryonic inner ear[2] "Due to the extreme inaccessibility of fetal human inner ear tissue, defining of the microRNAs (miRNAs) that regulate development of the inner ear has relied on animal tissue. In the present study, we performed the first miRNA sequencing of otic precursors in human specimens. Using HTG miRNA Whole Transcriptome assays, we examined miRNA expression in the cochleovestibular ganglion (CVG), neural crest (NC), and otic vesicle (OV) from paraffin embedded (FFPE) human specimens in the Carnegie developmental stages 13, 14 and 15. We found that in human embryonic tissues, there are different patterns of miRNA expression in the CVG, NC and OV. In particular, members of the miR-183 family (miR-96, miR-182, and miR-183) are differentially expressed in the CVG compared to NC and OV at Carnegie developmental stage 13. We further identified transcription factors that are differentially targeted in the CVG compared to the other tissues from stages 13-15, and we performed gene set enrichment analyses to determine differentially regulated pathways that are relevant to CVG development in humans. These findings not only provide insight into the mechanisms governing the development of the human inner ear, but also identify potential signaling pathways for promoting regeneration of the spiral ganglion and other components of the inner ear." (More? Hearing - Inner Ear Development)
  • MicroRNA dynamics at the onset of primordial germ and somatic cells sex differentiation during mouse embryonic gonad development[5] "In mammals, commitment and specification of germ cell lines implies involves complex programs that include sex differentiation, control of proliferation and meiotic initiation. Regulation of these processes is genetically controlled by fine-tuned mechanisms of gene regulation in which microRNAs (miRNAs) are involved. We have characterized, by small-RNAseq and bioinformatics analyses, the miRNA expression patterns of male and female mouse Primordial Germ Cells (PGCs) and gonadal somatic cells at embryonic stages: E11.5, E12.5 and E13.5. Differential expression analyses revealed differences in the regulation of key miRNA clusters such as miR-199-214, miR-182-183-96 and miR-34c-5p whose targets have defined roles during gonadal sexual determination in both germ and somatic cells." Primordial Germ Cell Development
  • Signs of embryo-maternal communication: miRNAs in the maternal serum of pregnant pigs[6] "Circulating miRNAs were proposed to be indicators of normal or complicated pregnancies. Based on this knowledge and our recent transcriptomic approach showing expression of miRNAs in the porcine endometrium, conceptuses and uterine extracellular vesicles during pregnancy, we have hypothesized that signs of ongoing local embryo-maternal crosstalk involving miRNAs can be detected in the circulation of pregnant gilts as early as a few days after maternal recognition of pregnancy. By applying several molecular biology techniques that differ in dynamic range and precision in maternal serum of Day 16 pregnant pigs, we were able to show for the first time increased levels of several miRNAs, previously reported to be expressed in either conceptuses and extracellular vesicles (miR-26a and miR-125b) or pregnant endometrium (miR-23b). Our results clearly showed that real-time RT-PCR and digital PCR are the most reliable methods, being able to detect small-fold changes of low-abundant circulating miRNAs. Further validation in a separate group of gilts confirmed an increase in miR-23b and miR-125b levels. In silico analyses identified pregnancy-related biological processes and pathways affected by these miRNAs. Target prediction analysis revealed hundreds of porcine transcripts with conserved sites for these miRNAs, which were classified into signaling pathways relevant to pregnancy. We conclude that a unique set of miRNAs can already be observed in the circulation of pigs during the first weeks of pregnancy, as a result of the initiation of embryo-maternal communication." Pig Development
  • MicroRNA Expression during Bovine Oocyte Maturation and Fertilization[7] "In order to further explore the roles of miRNAs in oocyte maturation, we employed small RNA sequencing as a screening tool to identify and characterize miRNA populations present in pools of bovine germinal vesicle (GV) oocytes, metaphase II (MII) oocytes, and presumptive zygotes (PZ). Each stage contained a defined miRNA population, some of which showed stable expression while others showed progressive changes between stages that were subsequently confirmed by quantitative reverse transcription polymerase chain reaction (RT-PCR). Bta-miR-155, bta-miR-222, bta-miR-21, bta-let-7d, bta-let-7i, and bta-miR-190a were among the statistically significant differentially expressed miRNAs (p < 0.05). To determine whether changes in specific primary miRNA (pri-miRNA) transcripts were responsible for the observed miRNA changes, we evaluated pri-miR-155, -222 and let-7d expression. Pri-miR-155 and -222 were not detected in GV oocytes but pri-miR-155 was present in MII oocytes, indicating transcription during maturation. In contrast, levels of pri-let-7d decreased during maturation, suggesting that the observed increase in let-7d expression was likely due to processing of the primary transcript. This study demonstrates that both dynamic and stable populations of miRNAs are present in bovine oocytes and zygotes and extend previous studies supporting the importance of the small RNA landscape in the maturing bovine oocyte and early embryo." Bovine Development
  • Maternal peripheral blood natural killer cells incorporate placenta-associated microRNAs during pregnancy[3] "Although recent studies have demonstrated that microRNAs (miRNAs or miRs) regulate fundamental natural killer (NK) cellular processes, including cytotoxicity and cytokine production, little is known about the miRNA‑gene regulatory relationships in maternal peripheral blood NK (pNK) cells during pregnancy. ...Twenty‑five miRNAs, including six C19MC miRNAs, were significantly upregulated in the third‑ compared to first‑trimester pNK cells. The rapid clearance of C19MC miRNAs also occurred in the pNK cells following delivery. Nine miRNAs, including eight C19MC miRNAs, were significantly downregulated in the post‑delivery pNK cells compared to those of the third‑trimester. DNA microarray analysis identified 69 NK cell function‑related genes that were differentially expressed between the first‑ and third‑trimester pNK cells. On pathway and network analysis, the observed gene expression changes of pNK cells likely contribute to the increase in the cytotoxicity, as well as the cell cycle progression of third‑ compared to first‑trimester pNK cells. Thirteen of the 69 NK cell function‑related genes were significantly downregulated between the first‑ and third‑trimester pNK cells. Nine of the 13 downregulated NK‑function‑associated genes were in silico target candidates of 12 upregulated miRNAs, including C19MC miRNA miR‑512‑3p. The results of this study suggest that the transfer of placental C19MC miRNAs into maternal pNK cells occurs during pregnancy."
  • Potential Regulatory Role of MicroRNAs in the Development of Bovine Gastrointestinal Tract during Early Life[3] "This study aimed to investigate the potential regulatory role of miRNAs in the development of gastrointestinal tract (GIT) during the early life of dairy calves. Rumen and small intestinal (mid-jejunum and ileum) tissue samples were collected from newborn (30 min after birth; n = 3), 7-day-old (n = 6), 21-day-old (n = 6), and 42-day-old (n = 6) dairy calves. The miRNA profiling was performed using Illumina RNA-sequencing and the temporal and regional differentially expressed miRNAs were further validated using qRT-PCR. ...The present study revealed temporal and regional changes in miRNA expression and a correlation between miRNA expression and microbial population in the GIT during the early life, which provides further evidence for another mechanism by which host-microbial interactions play a role in regulating gut development."
  • A survey of small RNAs in human sperm[8] "Bioinformatic analysis revealed the presence of multiple classes of small RNAs in human spermatozoa. The primary classes resolved included microRNA (miRNAs) (≈7%), Piwi-interacting piRNAs (≈17%), repeat-associated small RNAs (≈65%). A minor subset of short RNAs within the transcription start site/promoter fraction (≈11%) frames the histone promoter-associated regions enriched in genes of early embryonic development. These have been termed quiescent RNAs. CONCLUSIONS A complex population of male derived sncRNAs that are available for delivery upon fertilization was revealed. Sperm miRNA-targeted enrichment in the human oocyte is consistent with their role as modifiers of early post-fertilization. The relative abundance of piRNAs and repeat-associated RNAs suggests that they may assume a role in confrontation and consolidation. This may ensure the compatibility of the genomes at fertilisation."
More recent papers  
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MicroRNA formation
MicroRNA formation[1]

Pathway

  1. Primary miRNA precursors are transcribed in the nucleus
  2. Processed into 19-22 nt mature miRNAs by
    1. nuclear RNase III enzyme Drosha and its co-factor Dgcr8
    2. cytoplasmic RNase III enzyme Dicer
  3. miRNAs then loaded into the miRNA-induced silencing complex (miRISC)


Some miRNA subclasses are either Drosha- or Dicer-independent.

miRNA-Induced Silencing Complex

(miRISC) components include the argonaute proteins (Ago1–4), Ago2 is the only protein with the slicer activity.

Functional miRNA Grouping

The following identifies microRNAs that have been identified with specific developmental processes, based upon a commercial collation of basic research data.

  • Pluripotency
    • let-7a, let-7b, let-7c, let-7d, let-7e, let-7g, miR-101, miR-106b, miR-125b, miR-130a, miR-133b, miR-141, miR-15a, miR-17, miR-182, miR-183, miR-18a, miR-18b, miR-205, miR-20a, miR-20b, miR-21, miR-214, miR-22, miR-222, miR-23b, miR-24, miR-302a, miR-302c, miR-345, miR-424, miR-498, miR-518b, miR-520g.
  • miR-10 - microRNA precursor part of an RNA gene family which contains miR-10, miR-51, miR-57, miR-99 and miR-100. miR-10, miR-99 and miR-100 have been confirmed in a wide range of species.

Nomenclature

arm the mature sequence

  • left (-5p)
  • right (-3p)

Early Development

Ectoderm

  • Neural Development
    • let-7b, miR-103a, miR-106b, miR-10b, miR-124, miR-125b, miR-130a, miR-132, miR-134, miR-137, miR-16, miR-181a, miR-182, miR-183, miR-20a, miR-210, miR-219-5p, miR-22, miR-23b, miR-24, miR-26a, miR-302a, miR-302c, miR-7, miR-9, miR-96.
    • Neural Tube - miRNA-430 organises cell division (planes) for neural tube morphogenesis. PMID 26658217
  • Eye Development
    • miR-130a, miR-196a, miR-219-5p, miR-23b, miR-96.
  • Epidermal Differentiation
    • let-7b, miR-205, miR-210, miR-23b, miR-26a.
  • Inner Ear Development
    • miR-182, miR-183, miR-96.
  • Integumentary Development
    • 70 miRNAs are expressed in embryonic skin.
    • miR-205 in epithelia and promotes keratinocyte migration in vitro
    • miR-203 in suprabasal epidermal cells

Mesoderm

  • Haematopoiesis
    • let-7e, miR-125a-5p, miR-142-3p, miR-223.
  • T Cell Development
    • let-7a, let-7f, miR-106b, miR-142-5p, miR-146b-5p, miR-150, miR-15a, miR-15b, miR-16, miR-181a, miR-20a, miR-222, miR-26a.
  • Erythropoiesis
    • let-7a, let-7b, let-7c, let-7d, let-7f, let-7g, let-7i, miR-126, miR-128a, miR-137, miR-155, miR-15b, miR-16, miR-17, miR-181a, miR-182, miR-185, miR-206, miR-21, miR-22, miR-222, miR-24, miR-26a, miR-96.
  • Lymphopoiesis
    • let-7b, miR-125b, miR-128a, miR-16, miR-181a, miR-21, miR-24.
  • Megakaryopoiesis
    • miR-106b, miR-10a, miR-10b, miR-122, miR-126, miR-127-5p, miR-129-5p, miR-134, miR-146a, miR-150, miR-155, miR-17, miR-18a, miR-192, miR-20a, miR-20b, miR-21, miR-22, miR-301a, miR-33a, miR-378, miR-92a, miR-93.
  • Monocyte Differentiation
    • miR-155, miR-222, miR-424.
  • Myelopoiesis
    • miR-103a, miR-128a, miR-17, miR-181a, miR-24.
  • Angiogenesis
    • miR-126, miR-130a, miR-218, miR-222, miR-92a.
  • Myogenesis
    • miR-1, miR-125b, miR-206, miR-26a.
  • Osteogenesis
    • miR-141, miR-15b, miR-424.
  • Adipogenesis
    • let-7b, let-7c, let-7e, miR-100, miR-101, miR-103a, miR-10b, miR-146b-5p, miR-155, miR-182, miR-192, miR-194, miR-196a, miR-21, miR-210, miR-214, miR-22, miR-24, miR-498, miR-96, miR-99a.
  • Chondrogenesis: let-7f, miR-1, miR-132, miR-181a, miR-196a, miR-96, miR-99a.
  • Heart Development: miR-1, miR-208, miR-488.

Endoderm

  • Liver Development
    • let-7a, let-7b, let-7c, miR-10a, miR-122, miR-125b, miR-192, miR-21, miR-22, miR-23b, miR-92a, miR-99a.
  • Pancreatic Development
    • miR-15a, miR-15b, miR-16, miR-195, miR-214, miR-375, miR-7, miR-9.
  • Intestinal Development
    • let-7d, let-7e, miR-103a, miR-106b, miR-125b, miR-126, miR-130a, miR-141, miR-146b-5p, miR-17, miR-192, miR-194, miR-21, miR-215, miR-301a, miR-424.


Data: SABiosciences Cell Differentiation & Development miRNA PCR Array


Nucleolus

Five miRNAs show highest nucleolar concentration in myoblasts using the microarray assay, miR-340-5p, miR-351, miR-494, miR-664, or let-7e, are thought to be skeletal muscle-specific miRNAs (i.e., miR-1, miR-133, and miR-206 and perhaps miR-95, miR-128a, and miR-499).[9]


Sex Determination

microRNA shown in mouse genital development (miR-199-214, miR-182-183-96, and miR-34c-5p)[5]


Hearing

  • miR-183 family (miR-96, miR-182, and miR-183) are differentially expressed in the cochleovestibular ganglion compared to neural crest and otic vesicle at Carnegie stage 13. From a recent study of microRNAs in the human embryonic inner ear during Carnegie developmental stages 13, 14 and 15.[2]
  • miR-194 regulates the development and differentiation of sensory patches and statoacoustic ganglion of inner ear by fgf4.

From an earlier study in mouse[10] and a recent study of microRNAs in the zebrafish embryonic inner ear.[11]



Links: Hearing - Inner Ear Development

Other RNAs

The original "RNA family" consisted of just 3 main members; transfer RNA (tRNA), ribosomal RNA (rRNA) and messenger RNAs (mRNA). MicroRNA (miRNA) is a member of other newly identified classes of RNA have been suggested to have many different roles in signalling, protein processing and differentiation.

  • long non-coding RNA - (lncRNA) A class of RNA greater than 200bp in length that do not encode a protein product.[12]
  • small nuclear RNA - (snRNA)
  • small nucleolar RNA - (snoRNA)
  • short regulatory RNA (piwi-associated RNA (piRNA)
  • endogenous short-interfering RNA - (endo-siRNA)
  • microRNA - (miRNA)


References

  1. 1.0 1.1 Deiuliis JA. (2016). MicroRNAs as regulators of metabolic disease: pathophysiologic significance and emerging role as biomarkers and therapeutics. Int J Obes (Lond) , 40, 88-101. PMID: 26311337 DOI.
  2. 2.0 2.1 2.2 Chadly DM, Best J, Ran C, Bruska M, Woźniak W, Kempisty B, Schwartz M, LaFleur B, Kerns BJ, Kessler JA & Matsuoka AJ. (2018). Developmental profiling of microRNAs in the human embryonic inner ear. PLoS ONE , 13, e0191452. PMID: 29373586 DOI.
  3. 3.0 3.1 3.2 Liang G, Malmuthuge N, McFadden TB, Bao H, Griebel PJ, Stothard P & Guan le L. (2014). Potential regulatory role of microRNAs in the development of bovine gastrointestinal tract during early life. PLoS ONE , 9, e92592. PMID: 24682221 DOI.
  4. Svoboda P. (2017). Long and small noncoding RNAs during oocyte-to-embryo transition in mammals. Biochem. Soc. Trans. , 45, 1117-1124. PMID: 28939692 DOI.
  5. 5.0 5.1 Fernández-Pérez D, Brieño-Enríquez MA, Isoler-Alcaraz J, Larriba E & Del Mazo J. (2018). MicroRNA dynamics at the onset of primordial germ and somatic cell sex differentiation during mouse embryonic gonad development. RNA , 24, 287-303. PMID: 29187591 DOI.
  6. Reliszko ZP, Gajewski Z & Kaczmarek MM. (2017). Signs of embryo-maternal communication: miRNAs in the maternal serum of pregnant pigs. Reproduction , 154, 117-128. PMID: 28592665 DOI.
  7. Gilchrist GC, Tscherner A, Nalpathamkalam T, Merico D & LaMarre J. (2016). MicroRNA Expression during Bovine Oocyte Maturation and Fertilization. Int J Mol Sci , 17, 396. PMID: 26999121 DOI.
  8. Krawetz SA, Kruger A, Lalancette C, Tagett R, Anton E, Draghici S & Diamond MP. (2011). A survey of small RNAs in human sperm. Hum. Reprod. , 26, 3401-12. PMID: 21989093 DOI.
  9. Politz JC, Hogan EM & Pederson T. (2009). MicroRNAs with a nucleolar location. RNA , 15, 1705-15. PMID: 19628621 DOI.
  10. Wang XR, Zhang XM, Zhen J, Zhang PX, Xu G & Jiang H. (2010). MicroRNA expression in the embryonic mouse inner ear. Neuroreport , 21, 611-7. PMID: 20467336 DOI.
  11. Cao H, Shi J, Du J, Chen K, Dong C, Jiang D & Jiang H. (2018). MicroRNA-194 Regulates the Development and Differentiation of Sensory Patches and Statoacoustic Ganglion of Inner Ear by Fgf4. Med. Sci. Monit. , 24, 1712-1723. PMID: 29570699
  12. Goff LA & Rinn JL. (2015). Linking RNA biology to lncRNAs. Genome Res. , 25, 1456-65. PMID: 26430155 DOI.

Reviews

Wan Y, Kertesz M, Spitale RC, Segal E & Chang HY. (2011). Understanding the transcriptome through RNA structure. Nat. Rev. Genet. , 12, 641-55. PMID: 21850044 DOI.

Sayed D & Abdellatif M. (2011). MicroRNAs in development and disease. Physiol. Rev. , 91, 827-87. PMID: 21742789 DOI.

Yi R & Fuchs E. (2011). MicroRNAs and their roles in mammalian stem cells. J. Cell. Sci. , 124, 1775-83. PMID: 21576351 DOI.

Agirre E & Eyras E. (2011). Databases and resources for human small non-coding RNAs. Hum. Genomics , 5, 192-9. PMID: 21504869

Suh N & Blelloch R. (2011). Small RNAs in early mammalian development: from gametes to gastrulation. Development , 138, 1653-61. PMID: 21486922 DOI.

Ghildiyal M & Zamore PD. (2009). Small silencing RNAs: an expanding universe. Nat. Rev. Genet. , 10, 94-108. PMID: 19148191 DOI.

Articles

Mujahid S, Logvinenko T, Volpe MV & Nielsen HC. (2013). miRNA regulated pathways in late stage murine lung development. BMC Dev. Biol. , 13, 13. PMID: 23617334 DOI.

Dong J, Jiang G, Asmann YW, Tomaszek S, Jen J, Kislinger T & Wigle DA. (2010). MicroRNA networks in mouse lung organogenesis. PLoS ONE , 5, e10854. PMID: 20520778 DOI.

Hsu SD, Chu CH, Tsou AP, Chen SJ, Chen HC, Hsu PW, Wong YH, Chen YH, Chen GH & Huang HD. (2008). miRNAMap 2.0: genomic maps of microRNAs in metazoan genomes. Nucleic Acids Res. , 36, D165-9. PMID: 18029362 DOI.


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Cite this page: Hill, M.A. (2019, September 18) Embryology Molecular Development - microRNA. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Molecular_Development_-_microRNA

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