Alternative titles; symbols
HGNC Approved Gene Symbol: UCN
Cytogenetic location: 2p23.3 Genomic coordinates (GRCh38) : 2:27,307,400-27,308,445 (from NCBI)
Vaughan et al. (1995) described a rat cDNA for a member of the corticotropin-releasing hormone (CRH; 122560) family that is expressed in a region of the rat midbrain. The deduced peptide is 63% identical to fish urotensin and 45% identical to CRH. Synthetic urocortin was shown to cause secretion of ACTH (176830) and to bind to CRH receptor-1 (122561). The authors showed that the peptide also bound CRH receptor-2 (602034) better than CRH itself.
Using a placental genomic library, Donaldson et al. (1996) cloned the human counterpart of rat urocortin. The human gene encodes a deduced 124-amino acid protein with an 80-amino acid precursor that is 2 amino acids longer than rat Ucn. The mature human and rat proteins share 77% sequence identity. Synthetic human urocortin binds with high affinity to CRH receptors (122561) and acts in vitro to release ACTH from dispersed rat anterior pituitary cells. In addition, Donaldson et al. (1996) noted that the CRH-binding protein (122559) binds human urocortin with high affinity and can prevent urocortin-stimulated ACTH secretion in vitro.
Zhao et al. (1998) determined that both the human and mouse UCN genes contain 2 exons, and that the entire coding region is located in exon 2. They also identified several putative transcription factor-binding sites in the promoter region, including a TATA box, a cAMP response element (CRE), GATA-binding sites, a C/EBP (116897)-binding site, and a BRN2 (600494)-binding site. Transient transfection of a reporter construct containing the mouse promoter into PC12 cells revealed control of Ucn expression by both positive and negative elements; the CRE controlled basal activity as well as responsiveness to forskolin stimulation.
The neuropeptide CRH acts on the central nervous system in ways that mimic stress and result in decreases in exploration, increases in sympathetic activity, decreases in parasympathetic outflow, and decreases in appetitive behavior. Spina et al. (1996) demonstrated that urocortin binds with high affinity to the CRF2 receptor, is more potent than CRF in suppressing appetite, but is less potent than CRF in producing anxiety-like effects and activation. Doses as low as 10 nanograms injected intracerebroventricularly were effective in decreasing food intake in food-deprived and free-feeding rats. These results suggested to them that urocortin may be an endogenous CRF-like factor in the brain responsible for the effects of stress on appetite.
Donaldson et al. (1996) mapped the UCN gene to chromosome 2 by Southern blot analysis of human/rodent somatic cell hybrids. Using radiation hybrid analysis, Delplanque et al. (2002) mapped the UCN gene to chromosome 2p23-p21.
Zhao et al. (1998) located the MPV17 gene (137960), transcribed in the same orientation, in the 5-prime region about 1.3 kb upstream of the UCN gene. Mouse Mpv17 mapped about 2.1 kb upstream of the Ucn gene. Based on the previous localization of Mpv17, they mapped mouse Ucn to chromosome 5.
Linkage between obesity-related phenotypes and the 2p23-p21 locus has been reported. The UCN gene resides at this interval, and its protein decreases appetite behavior, suggesting that UCN may be a candidate gene for susceptibility to obesity. Delplanque et al. (2002) localized the UCN gene by radiation hybrid mapping, and the surrounding markers were genotyped in a collection of French families. Evidence for linkage was shown between the marker D2S165 and leptin (164160) levels (lod score, 1.34; P equal to 0.006) and between D2S2247 and the z-score of body mass index (lod score, 1.829; P equal to 0.0019). The gene was screened for single-nucleotide polymorphisms (SNPs) in 96 obese patients. Four new variants were established. Two SNPs were located in the promoter, 1 in intron 1, and 1 in the 3-prime untranslated region. Association studies in cohorts of 722 unrelated obese and 381 control subjects and transmission disequilibrium tests, performed for the 2 frequent promoter polymorphisms, in 120 families (894 individuals) showed that no association was present between these variants and obesity, obesity-related phenotypes, and diabetes. The authors concluded that their analyses of the genetic variations of the UCN gene suggest that, at least in French Caucasians, the genetic variations do not represent a major cause of obesity.
Urocortin is a member of the corticotropin-releasing peptide family. The distinct expression pattern in discrete brain regions suggests that it influences such behavior as feeding, anxiety, and auditory processing. To better define the physiologic roles of urocortin, Vetter et al. (2002) generated mice carrying a null mutation of the urocortin gene. Urocortin-deficient mice had normal basal feeding behavior and stress responses, but showed heightened anxiety-like behaviors in the elevated plus maze and open-field tests. In addition, hearing was impaired in the mutant mice at the level of the inner ear, suggesting that urocortin is involved in the normal development of cochlear sensory-cell function. These results provided the first example of a function for any peptidergic system in hearing. In contrast to these findings, Wang et al. (2002) found that Ucn-deficient mice exhibited normal anxiety-like behavior and normal autonomic regulation in response to stress. The mutant mice displayed an impaired acoustic startle response that was not due to an obvious hearing defect. By in situ hybridization, they found Unc expressed predominantly in the Edinger-Westphal nucleus, suggesting that Ucn may modulate the acoustic startle response through neuronal projections from this region.
Delplanque, J., Vasseur, F., Durand, E., Abderrahmani, A., Dina, C., Waeber, G., Guy-Grand, B., Clement, K., Weill, J., Boutin, P., Froguel, P. Mutation screening of the urocortin gene: identification of new single nucleotide polymorphisms and association studies with obesity in French Caucasians. J. Clin. Endocr. Metab. 87: 867-869, 2002. [PubMed: 11836334] [Full Text: https://doi.org/10.1210/jcem.87.2.8259]
Donaldson, C. J., Sutton, S. W., Perrin, M. H., Corrigan, A. Z., Lewis, K. A., Rivier, J. E., Vaughan, J. M., Vale, W. W. Cloning and characterization of human urocortin. Endocrinology 137: 2167-2170, 1996. Note: Erratum: Endocrinology 137: 3896 only, 1996. [PubMed: 8612563] [Full Text: https://doi.org/10.1210/endo.137.5.8612563]
Spina, M., Merlo-Pich, E., Chan, R. K. W., Basso, A. M., Rivier, J., Vale, W., Koob, G. F. Appetite-suppressing effects of urocortin, a CRF-related neuropeptide. Science 273: 1561-1564, 1996. [PubMed: 8703220] [Full Text: https://doi.org/10.1126/science.273.5281.1561]
Vaughan, J., Donaldson, C., Rittencourt, J., Porrin, M. H., Lewis, K., Sutton, S., Chan, R., Turnbull, A. V., Lovejoy, D., Rivier, C., Rivier, J., Sawchenko, P. E., Vale, W. The mammalian neuropeptide urocortin, related to fish urotensin I and to corticotropin-releasing factor. Nature 378: 287-292, 1995. [PubMed: 7477349] [Full Text: https://doi.org/10.1038/378287a0]
Vetter, D. E., Li, C., Zhao, L., Contarino, A., Liberman, M. C., Smith, G. W., Marchuk, Y., Koob, G. F., Heinemann, S. F., Vale, W., Lee, K.-F. Urocortin-deficient mice show hearing impairment and increased anxiety-like behavior. Nature Genet. 31: 363-369, 2002. [PubMed: 12091910] [Full Text: https://doi.org/10.1038/ng914]
Wang, X., Su, H., Copenhagen, L. D., Vaishnav, S., Pieri, F., Shope, C. D., Brownell, W. E., De Biasi, M., Paylor, R., Bradley, A. Urocortin-deficient mice display normal stress-induced anxiety behavior and autonomic control but an impaired acoustic startle response. Molec. Cell. Biol. 50: 6605-6610, 2002.
Zhao, L., Donaldson, C. J., Smith, G. W., Vale, W. W. The structures of the mouse and human urocortin genes (Ucn and UCN). Genomics 50: 23-33, 1998. [PubMed: 9628819] [Full Text: https://doi.org/10.1006/geno.1998.5292]