In molecular biology miR-132 microRNA 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 ...

molecule.

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 function to regulate the expression levels of other genes by several mechanisms, generally reducing protein levels through the cleavage of mRNAs or the repression of their translation. Several targets for miR-132 have been described, including mediators of neurological development,

synaptic transmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

and

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

Expression

miR-132 arises from the miR-212/132 cluster located in the intron of a non-coding gene on mouse chromosome 11. The transcription of this cluster was found to be enhanced by the transcription factor

CREB CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...

(cAMP-response element binding protein). In neuronal cells

BDNF Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...

(brain derived neurotrophic factor) is known to induce the transcription of this cluster; the pathway is thought to involve the BDNF-mediated activation of ERK1/2, which in turn activates MSK, another

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

enzyme. MSK-mediated phosphorylation of a serine residue on CREB may then enhance production of miR-132. MSK knockout mice still produce miR-132 in response to BDNF, but at a significantly lower level, indicating that there may be an alternative pathway operating. Activators of CREB phosphorylation, for instance

forskolin Forskolin (coleonol) is a labdane diterpene produced by the plant ''Coleus barbatus'' (Blue Spur Flower). Other names include pashanabhedi, Indian coleus, makandi, HL-362, mao hou qiao rui hua. As with other members of the large diterpene class of ...

and KSHV binding to endothelial cell targets, can also enhance miR-132 production in vitro. miR-132 levels are increased post-seizure, which strongly suggests a causal relationship between neuronal activation and miR-132 transcription. One example of this phenomenon is in the

suprachiasmatic nucleus The suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regula ...

, where miR-132 is thought be involved in resetting the

circadian clock A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase (waves), phase and is synchronized with solar time. Such a clock's ''in vivo'' period is necessarily almost exactly 24 hours (the earth's curre ...

in response to light. Inflammatory mediators such as

Lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...

(LPS) are also implicated in inducing miR-132 expression.

Role in neuronal cells

miR-132 is enriched in neuronal cells. Recognition elements for this miRNA have been identified in a number of cellular mRNAs. One such mRNA is that of p250GAP, a

GTPase activating protein GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G protein G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that a ...

linked to neuronal differentiation. miR-132 and its recognition site on p250GAP mRNA are highly conserved among vertebrates, and their interaction is suspected to have a role in vertebrate

neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...

. By decreasing the levels of p250GAP, miR-132 promotes neuronal outgrowth and sprouting. Another target for miR-132 is

MeCP2 ''MECP2'' (methyl CpG binding protein 2) is a gene that encodes the protein MECP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in ...

, whose mRNA is expressed as a 'long' variant in neuronal cells. This variant contains a recognition element for miR-132 in its extended 3'UTR. miRNA-132 may be involved in a homeostatic mechanism that regulates MeCP2 levels in the brain. MeCP2 increases the levels of BDNF in the brain, which in turn will increase transcription from the miR-212/132 cluster. A rise in miRNA-132 level will then decrease the levels of MeCP2 and restore the balance. Failure to regulate MeCP2 levels is connected to neurological disorders including

Rett syndrome Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in females. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often h ...

. The role of miR-132 in synaptic function is currently being studied. A BDNF-related increase in miR-132 is thought to bring about an increase in post-synaptic protein levels. miR-132 has been found to associate with Fragile X Mental Retardation Protein

FMRP ''FMR1'' (Fragile X Messenger Ribonucleoprotein 1) is a human gene that codes for a protein called ''fragile X messenger ribonucleoprotein'', or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development ...

, and may be involved in the selection of mRNAs, including those regulating synaptic function, to undergo translational suppression via an FMRP-dependent mechanism. miR-132 may also be responsible for limiting inflammation in the brain. A recognition sequence for this miRNA can be found in the mRNA for

acetylcholinesterase Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme Enzymes () are proteins that a ...

(AChE), that degrades

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...

(ACh). By silencing the expression of AChE, ACh levels rise and inhibit peripheral inflammation.

Infection and inflammation

Outside the brain, miR-132 can also modulate inflammation; transcription is stimulated by LPS and upregulated at a fairly early stage of herpesvirus infection. KSHV infection of endothelial cells, as well as

HSV-1 Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...

HCMV ''Human betaherpesvirus 5'', also called human cytomegalovirus (HCMV), is species of virus in the genus ''Cytomegalovirus'', which in turn is a member of the viral family known as ''Herpesviridae'' or herpesviruses. It is also commonly called ...

infection of monocytes, have been observed to induce this rise. In this instance, the target of translational suppression appears to be p300, a protein that associates with CREB and is an important mediator of antiviral immunity. By decreasing the levels of p300, the expression of

IFN-β The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...

ISG15 Interferon-stimulated gene 15 (ISG15) is a 17 kDA secreted protein that in humans is encoded by the ''ISG15'' gene. ISG15 is induced by type I interferon (IFN) and serves many functions, acting both as an extracellular cytokine and an intracellul ...

IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...

and IL6 is impaired, resulting in the net suppression of antiviral immunity. miR-132 is only transiently induced following infection; the silencing of p300 results in a reduction in CREB-mediated transcription from the miR-212/132 cluster, thus forming a negative feedback loop. Plasma from patients with

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

(RA) has been found to contain lower levels of miR-132 compared to samples from healthy individuals. As RA is an autoimmune, inflammatory disease, it is possible that miR-132 helps to regulate inflammation in healthy joints. Conversely, miR-132 has been implicated in promoting inflammation in adipocytes. The target for RNA silencing in this case is

SirT1 Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene. SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (''S. cerevisiae''), referring to the fact t ...

, a deacetylase enzyme. The p65 subunit of

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

is a SirT1 substrate; in the absence of SirT1 activity, NFκB is active, promoting inflammation and the production of the chemokines IL-8 and

MCP-1 ''For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.'' The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL ...

. This process is implicated in the chronic inflammation that may underlie

insulin resistance Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...

in the obese, and may occur in response to serum deprivation.

Angiogenesis and cancer

miR-132 can induce the proliferation of endothelial cells and has been implicated in neovascularisation.

Angiogenic Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

factors such as

VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

and

bFGF Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor receptor ''(FG ...

are CREB activators which could theoretically induce miR-132 production in endothelial cells. Here, the miRNA can silence the expression of p120RasGAP, fixing

Ras Ras or RAS may refer to: Arts and media * RAS Records Real Authentic Sound, a reggae record label * Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service * Rás 1, an Icelandic radio station * Rás 2, an Icelandic radio stati ...

in a GTP-bound, active conformation so as to induce proliferation. This angiogenic role could implicate miR-132 in oncogenesis, and this miRNA is known to be overexpressed in chronic lymphoblastic leukaemias. miR-132 also comprises part of the recently identified miRNA 'signature' of mammalian osteosarcoma, although a direct role in oncogenesis is yet to be fully described.

Heart pathology

MiR-132 has been found to inhibit cardiac pathology in rodents.

Other targets

The

Angiotensin II receptor type 1 Angiotensin II receptor type 1 (AT1) is the best characterized angiotensin receptor. It is encoded in humans by the ''AGTR1'' gene. AT1 has vasopressor effects and regulates aldosterone secretion. It is an important effector controlling blood pr ...

mRNA also undergoes miR-132-mediated silencing.

KIAA1211L KIAA1211L is a protein that in humans is encoded by the KIAA1211L gene. It is highly expressed in the brain (Cerebral cortex, Cerebral Cortex). Furthermore, it is localized to the microtubules and the centrosomes and is subcellularly located in the ...

is also a predicted miR-132 target.

References

External links

* {{miRNA precursor families MicroRNA