The miR-199 microRNA precursor is a short

non-coding RNA A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non-c ...

gene involved in

gene regulation Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wide ...

. miR-199 genes have now been predicted or experimentally confirmed in

mouse A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...

and a further 21 other species.

microRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...

s are transcribed as ~70

nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...

precursors and subsequently processed by the

Dicer Dicer, also known as endoribonuclease Dicer or helicase with RNase motif, is an enzyme that in humans is encoded by the gene. Being part of the RNase III family, Dicer cleaves double-stranded RNA (dsRNA) and pre-microRNA (pre-miRNA) into short d ...

enzyme to give a ~22 nucleotide product. The mature products are thought to have regulatory roles through complementarity to

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

Origin and evolution of miR-199

miR-199 has been shown to be a vertebrate specific miR family that emerge at the origin of the vertebrate lineage Desvignes, T; Postlethwait JH. 2013. Evolution of the miR199-214 cluster and vertebrate skeletal development. Submitted to RNA Biology. Three paralogs of miR-199 can usually be found in non-teleost vertebrate species and 4 to 5 copies in the teleost species. All miR-199 genes are located on opposite strand of orthologous intron of

Dynamin Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamin is part of the "dynamin superfamily", which includes classical dynamins, dynamin-like proteins, Mx proteins, OPA1, mitofusins, and GBPs. Members of the dynamin fa ...

genes. Within Dynamin3 gene (''Dnm3''), miR-199 is associated with

miR-214 __NOTOC__ miR-214 is a vertebrate-specific family of microRNA precursors. The ~22 nucleotide mature miRNA sequence is excised from the precursor hairpin by the enzyme Dicer. This sequence then associates with RISC which effects RNA interfere ...

and both miRs are transcribed together as a common primary transcript, demonstrated in mouse, human and zebrafish.

Targets and expression of miR-199

miR-199 has been shown to be implicated in a wide variety of cellular and developmental mechanisms such as various cancer development and progression, cardiomyocytes protection or skeletal formation. Using microarray and immunoblotting analyses it has been shown that miR-199a* targets the Met proto-oncogene. MicroRNA hsa-miR-199a is a regulator of IκB kinase-β (IKKβ) expression. Using

TaqMan TaqMan probes are hydrolysis probes that are designed to increase the specificity of quantitative PCR. The method was first reported in 1991 by researcher Kary Mullis at Cetus Corporation, and the technology was subsequently developed by Hoffmann ...

real-time quantitative PCR array methods, miRNA expression has been profiled. miR-199a, one of the most significantly overexpressed in invasive squamous cell carcinomas (ISCCs), was evaluated by transfecting cervical cancer cells (SiHa and ME-180) with anti-miR-199a oligonucleotides and the cell viability assessed. mirR-199a*, mir199a and mirR-199b were significantly overexpressed in ISCCs.

Implication of miR-199 in skeletogenesis

miR-199, along with its cluster mate

MiR-214 __NOTOC__ miR-214 is a vertebrate-specific family of microRNA precursors. The ~22 nucleotide mature miRNA sequence is excised from the precursor hairpin by the enzyme Dicer. This sequence then associates with RISC which effects RNA interfere ...

, has been shown to be implicated in skeleton formation. In mice, miR-199 is expressed in perichondrial cells, periarticular chondrocytes, tracheal cartilage, limb

mesenchyme Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every o ...

, and most tissues in the upper and lower jaw. In zebrafish, miR-199 is expressed in the developing notochord and in all tissues surrounding developing skeletal elements. Comparative miRNA array led to the isolation of several Bone Morphogenic Protein 2 (BMP2)-responsive miRNAs. Among them, miR-199a* is of particular interest, because it was reported to be specifically expressed in the skeletal system and was shown to inhibit chondrogenesis by down-regulation of Smad1, a major regulator of bone and cartilage formation and development. Also, Twist-1, which is a major actor in skeleton formation, regulates miR-199 and miR-214 cluster expression in mouse. Furthermore, miR199-214 cluster deletion in mouse lead to skeletal development abnormalities including craniofacial defects, neural arch and spinous processes malformations, and osteopenia.

Clinical relevance of miR-199

Alcoholic liver disease Alcoholic liver disease (ALD), also called alcohol-related liver disease (ARLD), is a term that encompasses the liver manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and chronic hepatitis with liver fibrosis ...

is a common medical consequence of long-term excessive alcohol use. Activation of hypoxia-Inducible Factor-1α (HIF-1α) is an indicator of

hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...

. Endothelin-1 (ET-1) is a protein that constricts blood vessels and raises blood pressure. It has been shown that ethanol-induced miR-199 down-regulation may contribute to augmented HIF-1α and ET-1 expression.

References

External links