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NEUROMEDIN U; NMU

NEUROMEDIN U; NMU

HGNC Approved Gene Symbol: NMUCytogenetic location: 4q12 Genomic coordinates (GRCh38): 4:55,595,230-55,636,792 (from NCBI)▼ DescriptionNeuromedin U (NMU) is ...

HGNC Approved Gene Symbol: NMU

Cytogenetic location: 4q12 Genomic coordinates (GRCh38): 4:55,595,230-55,636,792 (from NCBI)

▼ Description
Neuromedin U (NMU) is a neuropeptide with potent activity on smooth muscle, which was isolated first from porcine spinal cord and later from other species. It is widely distributed in the gut and central nervous system. Peripheral activities of NMU include stimulation of smooth muscle, increase of blood pressure, alteration of ion transport in the gut, control of local blood flow, and regulation of adrenocortical function (summary by Howard et al., 2000).

▼ Cloning and Expression
The neuromedin U (NMU) peptide has potent uterine contractile effects. Cloning and characterization of the rat Nmu precursor cDNA (Lo et al., 1992) suggested that the Nmu precursor may generate other peptides in addition to the Nmu peptide. Using PCR methods, Austin et al. (1995) isolated human pituitary cDNAs encoding a deduced 174-amino acid NMU precursor that shares 70% amino acid sequence similarity with the rat Nmu precursor. The human NMU precursor contains a signal peptide and 4 paired basic residues, which are putative proteolytic processing sites, indicating that it may generate 3 peptides, including NMU. The 25-residue human NMU peptide is located near the C terminus of its precursor. One of the potential peptides, which consists of 33 residues, differs from the corresponding potential rat peptide by only 2 amino acids, suggesting that these peptides are biologically significant. The authors identified 2 additional, less abundant forms of human NMU precursor cDNA, each containing a different in-frame deletion. Northern blot analysis of human pituitary and colon demonstrated that NMU precursor mRNA is more abundant in pituitary. Northern blot analysis of tissues from various regions of the gastrointestinal tract showed that NMU precursor mRNA is expressed at a similar level throughout the tract. Among gastrointestinal tissues, radioimmunoassay (RIA) detected the highest level of NMU peptide in the jejunum.

▼ Gene Function
Howard et al. (2000) examined the distribution of NMU mRNA in rat brain and compared its expression in fasting and fed rats. NMU mRNA is discretely located, with the most abundant signals in the ventromedial hypothalamic regions (lateral, arcuate nucleus, and median eminence), and in the caudal brainstem. Colocalization studies indicated that NMU and POMC RNAs are expressed close to each other in the arcuate nucleus median eminence, but are not expressed in the same neurons. The expression of NMU in the ventromedial hypothalamus was reduced significantly in rats fasted for 48 hours when compared with fed rats. The decrease is similar to that observed for POMC and cocaine-amphetamine-regulated transcript (CART). In mouse, NMU expression was detected in the suprachiasmatic nucleus and appeared to be decreased in ob/ob mice. Weak NMU hybridization signals were also seen in the dorsomedial hypothalamic nucleus of mice. Howard et al. (2000) demonstrated that FM3 (NMUR1; 604153) and FM4 (NMUR2; 605108) are cognate receptors for NMU.

To elucidate the signals that direct type 2 innate lymphoid cells (ILC2s) to promote homeostasis versus inflammation, Wallrapp et al. (2017) used single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines Il25 (605658) and Il33 (608678) to profile mouse lung-resident ILCs. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic, and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after Il25 stimulation. Nmu, the ligand of Nmur1, activated ILC2s in vitro, and in vivo coadministration of Nmu with Il25 strongly amplified allergic inflammation. Loss of Nmu-Nmur1 signaling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Wallrapp et al. (2017) concluded that NMUR1 signaling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces.

Cardoso et al. (2017) showed that Nmu in mice is a fast and potent regulator of type 2 innate immunity in the context of a functional neuron-ILC2 unit. Cardoso et al. (2017) found that ILC2s selectively express Nmur1, and mucosal neurons expressed Nmu. Cell-autonomous activation of ILC2s with Nmu resulted in immediate and strong Nmur1-dependent production of innate inflammatory and tissue repair cytokines. Nmu controls ILC2s downstream of extracellular signal-regulated kinase (see ERK1, 601795) and calcium-influx-dependent activation of both calcineurin (see 114105) and the Nfat complex (see 600489). Nmu treatment in vivo resulted in immediate protective type 2 responses. Accordingly, ILC2-autonomous ablation of Nmur1 led to impaired type 2 responses and poor control of worm infection. Notably, mucosal neurons were found adjacent to ILC2s, and these neurons directly sensed worm products and alarmins to induce Nmu and to control innate type 2 cytokines. Cardoso et al. (2017) concluded that their work revealed that neuron-ILC2 cell units confer immediate tissue protection through coordinated neuroimmune sensory responses.

Klose et al. (2017) demonstrated that ILC2s in the mouse gastrointestinal tract colocalize with cholinergic neurons that express the neuropeptide Nmu. In contrast to other hematopoietic cells, ILC2s selectively express NMUR1. In vitro stimulation of ILC2s with Nmu induced rapid cell activation, proliferation, and secretion of the type 2 cytokines Il5 (147850), Il9 (146931), and Il13 (147683) that was dependent on cell-intrinsic expression of Nmur1 and G-alpha-q (GNAQ; 600998) protein. In vivo administration of Nmu triggered potent type 2 cytokine responses characterized by ILC2 activation, proliferation, and eosinophil recruitment that was associated with accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis or induction of lung inflammation. Conversely, worm burden was higher in Nmur1-null mice than in control mice. Furthermore, use of gene-deficient mice and adoptive cell transfer experiments revealed that ILC2s were necessary and sufficient to mount Nmu-elicited type 2 cytokine responses. Klose et al. (2017) concluded that the NMU-NMUR1 neuronal signaling circuit provides a selective mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce antimicrobial, inflammatory, and tissue-protective type 2 responses at mucosal sites.

▼ Mapping
The International Radiation Hybrid Mapping Consortium mapped the NMU gene to chromosome 4 (STS-X76029).

▼ Animal Model
Hanada et al. (2004) found that mice lacking the Nmu gene appeared normal and were fertile, but they progressively developed obesity with excessive caloric intake and decreased energy expenditure. Obese Nmu -/- mice developed hyperleptinemia, hyperinsulinemia, late-onset hyperglycemia, and hyperlipidemia. Core body temperature in mutant mice was significantly reduced, and mutants failed to induce thermogenesis after cold exposure. The results indicated that Nmu regulates feeding behavior and energy metabolism independent of the leptin signaling pathway.

Since NMUR1 is expressed in peripheral tissues, Moriyama et al. (2005) evaluated a potential immunoregulatory function for NMU using Nmu-deficient mice. Induction of mast cell-mediated inflammation by complete Freund adjuvant, manifested by edema and neutrophil infiltration, did not occur in Nmu -/- mice. Intraplantar injection of NMU induced mast cell degranulation, vasodilation, and plasma extravasation in wildtype and Nmu-deficient mice, but not in mast cell-deficient mice. RT-PCR analysis detected Nmu expression in mouse intestine and Nmur1 expression in intestine, peritoneal mast cells, and lung, but not spleen. Nmu induced calcium mobilization and degranulation in mast cells. Moriyama et al. (2005) concluded that NMU promotes mast cell-mediated inflammation and proposed that NMU receptor antagonists could be targets for pharmacologic inhibition of mast cell-mediated inflammatory diseases.

Sato et al. (2007) showed that Nmu -/- mice had higher bone mass than wildtype mice due to increased bone formation, and this effect was more prominent in male mice than female mice. Physiologic and cell-based assays revealed that Nmu acted in the central nervous system, rather than directly on bone cells, to regulate bone remodeling. Leptin (LEP; 164160)- or sympathetic nervous system-mediated inhibition of bone formation was abolished in Nmu -/- mice. Moreover, Nmu -/- mice showed altered bone expression of molecular clock genes that mediate the inhibition of bone formation by leptin. Treatment of wildtype mice with a natural agonist for Nmu receptor decreased bone mass. Sato et al. (2007) concluded that NMU is a central mediator of leptin-dependent regulation of bone mass.

Fukue et al. (2006) found that Nmu-deficient mice exhibited early-onset vaginal opening. The luteinizing hormone-beta (LHB; 152780)/follicle-stimulating hormone-beta (FSHB; 136435) ratio, an index of puberty onset, was high in young Nmu-deficient mice, and Nmu suppressed LH and FSH release from rat anterior pituitary cells. Fukue et al. (2006) concluded that NMU suppresses gonadotropin secretion and regulates onset of puberty.

Tags: 4q12