Details for: UCN3

Gene ID: 114131

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: UCN3

Ensembl ID: ENSG00000178473

Description: urocortin 3

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • pancreatic A cell CL0000171
    CSI 12.74
    rCSI 13.34%
    PRS 99.68
  • enteroendocrine cell of small intestine CL0009006
    CSI 12.22
    rCSI 26.91%
    PRS 99.69
  • ciliated cell CL0000064
    CSI 12.06
    rCSI 19.54%
    PRS 98.84
  • enteroendocrine cell CL0000164
    CSI 11.52
    rCSI 15.74%
    PRS 99.25
  • type L enteroendocrine cell CL0002279
    CSI 9.69
    rCSI 18.19%
    PRS 99.67
  • enteroendocrine cell of colon CL0009042
    CSI 9.47
    rCSI 44.41%
    PRS 99.62
  • type B pancreatic cell CL0000169
    CSI 4.8
    rCSI 10.62%
    PRS 99.52
  • ciliated columnar cell of tracheobronchial tree CL0002145
    CSI 1.25
    rCSI 2.84%
    PRS 98.89

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [UCN3](/details-gene/114131) (urocortin 3) is a protein-coding gene that encodes a neuropeptide hormone belonging to the corticotropin-releasing factor (CRF) family. As a secreted peptide, [UCN3](/details-gene/114131) functions as a high-affinity ligand primarily for the corticotropin-releasing hormone receptor 2 (CRFR2) ([Link](https://doi.org/10.1073/pnas.121165198)). Its expression is highly specific to discrete cell populations, most notably endocrine cells within the pancreas and gastrointestinal tract. Functionally, it is implicated in hormone-mediated signaling pathways that govern metabolic processes, such as the regulation of insulin secretion in response to glucose and nutrient levels, as well as cellular responses to stress. ## Cellular Roles and Expression Landscape The expression profile of [UCN3](/details-gene/114131) highlights its specialized role in endocrine and secretory cell types, primarily involved in metabolic regulation and homeostasis. **Overall**, the gene shows the highest significance and specificity in cells of the endocrine system. It is a defining marker for [pancreatic A cell](/details-cell/CL0000171) (CSI: 12.74), the glucagon-producing cells of the pancreatic islets. This is complemented by significant, though lower, expression in [type B pancreatic cell](/details-cell/CL0000169) (CSI: 4.80), suggesting a key role in the paracrine regulation of islet function. Furthermore, [UCN3](/details-gene/114131) is exceptionally prominent in the gut endocrine system, with very high significance scores in [enteroendocrine cell of small intestine](/details-cell/CL0009006) (CSI: 12.22), generic [enteroendocrine cell](/details-cell/CL0000164) (CSI: 11.52), [type L enteroendocrine cell](/details-cell/CL0002279) (CSI: 9.69), and [enteroendocrine cell of colon](/details-cell/CL0009042) (CSI: 9.47). This expression pattern points to a crucial role in gut-brain axis communication and the local regulation of digestion and nutrient sensing. Interestingly, [UCN3](/details-gene/114131) also shows high significance in [ciliated cell](/details-cell/CL0000064) (CSI: 12.06) and [ciliated columnar cell of tracheobronchial tree](/details-cell/CL0002145) (CSI: 1.25), suggesting a potential, less-characterized role in mucosal tissues, possibly related to local stress responses or modulation of ciliary function. ## Pathways and Molecular Function The molecular functions of [UCN3](/details-gene/114131) are centered on its activity as a signaling hormone. As an extracellular ligand ([GO:0005576](https://www.ebi.ac.uk/QuickGO/term/GO:0005576)), it exerts its effects by binding specifically to corticotropin-releasing hormone receptors, particularly CRFR2 ([GO:0051431](https://www.ebi.ac.uk/QuickGO/term/GO:0051431)). This interaction initiates downstream signaling cascades typical of G protein-coupled receptors (GPCRs), as annotated in Reactome pathways like [Signaling by gpcr](https://reactome.org/content/detail/R-HSA-372790) and [Class b/2 (secretin family receptors)](https://reactome.org/content/detail/R-HSA-373080). Consistent with its expression in pancreatic islets, [UCN3](/details-gene/114131) is directly involved in the [positive regulation of insulin secretion](/details-go/GO:0032024) and the [response to glucose](/details-go/GO:0009749). Its role extends to broader metabolic and stress responses, including the [cellular response to nutrient levels](/details-go/GO:0031669), [response to starvation](/details-go/GO:0042594), and [response to corticosterone](/details-go/GO:0051412), underscoring its function as a mediator between metabolic state and stress physiology. Its localization to the [axon terminus](/details-go/GO:0043679) further supports its role as a neuropeptide in cell-to-cell communication. ## Research Directions The highly specific expression of [UCN3](/details-gene/114131) in key metabolic and endocrine cells, combined with its function as a CRFR2 ligand, provides fertile ground for further investigation into its physiological roles and therapeutic potential. ### Proposed Hypotheses: 1. **Paracrine Regulation in Pancreatic Islets:** Given its high expression in [pancreatic A cell](/details-cell/CL0000171) and its established role in regulating insulin secretion, it is hypothesized that [UCN3](/details-gene/114131) acts as a critical paracrine signaling molecule within the islet of Langerhans, coordinating glucagon and insulin release from alpha and beta cells, respectively, to fine-tune glucose homeostasis. 2. **Gut-Brain Axis Signaling:** The strong expression in various [enteroendocrine cell](/details-cell/CL0000164) populations suggests that [UCN3](/details-gene/114131) is secreted into the lamina propria or bloodstream in response to nutrient ingestion, where it acts on local enteric neurons or distant targets in the brain to regulate appetite, gut motility, and overall energy balance. 3. **Mucosal Stress Response:** The unexpected high significance in [ciliated cell](/details-cell/CL0000064)s suggests a localized protective role. It is hypothesized that [UCN3](/details-gene/114131) is released by ciliated epithelial cells in the respiratory tract in response to stressors like hypoxia ([GO:0071456](https://www.ebi.ac.uk/QuickGO/term/GO:0071456)) or pathogens, where it modulates ciliary beat frequency and mucus clearance as part of the innate defense mechanism. ### Key Experimental Approach: To test the hypothesis of its paracrine role in pancreatic islets (Hypothesis 1), one could utilize an ex vivo model of isolated human or murine islets. These islets could be cultured and stimulated with varying glucose concentrations in the presence or absence of a specific CRFR2 antagonist. The supernatants would then be collected to measure insulin and glucagon secretion levels via ELISA. Furthermore, shRNA-mediated knockdown of [UCN3](/details-gene/114131) specifically in A-cells within these islets, followed by the same stimulation protocol, would provide direct evidence of its contribution to inter-islet cell communication. ### Therapeutic Potential: As a secreted peptide that interacts with a well-defined GPCR, the [UCN3](/details-gene/114131)-CRFR2 signaling axis presents a druggable target. Given its role in positively regulating insulin secretion, CRFR2 agonists that mimic the action of [UCN3](/details-gene/114131) could be explored as a potential therapeutic strategy for type 2 diabetes, aiming to enhance glucose-stimulated insulin release. Conversely, CRFR2 antagonists could be investigated for conditions characterized by inappropriate stress responses or metabolic dysregulation linked to the gut-brain axis, such as irritable bowel syndrome or stress-induced eating disorders. The high specificity of its expression may limit off-target effects, increasing its attractiveness as a therapeutic target.

Genular Protein ID: 2095133056

Symbol: UCN3_HUMAN

Name: Urocortin-3

UniProtKB Accession Codes:

Q969E3 Q496H2 Q5SR91

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 8 Ensembl 1 GO 18 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 2 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 SMR 1 STRING 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 11416224

Title: Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor.

PubMed ID: 11416224

DOI: 10.1073/pnas.121165198

PubMed ID: 11329063

Title: Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor.

PubMed ID: 11329063

DOI: 10.1038/87936

PubMed ID: 15164054

Title: The DNA sequence and comparative analysis of human chromosome 10.

PubMed ID: 15164054

DOI: 10.1038/nature02462

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 18052377

Title: Common and divergent structural features of a series of corticotropin releasing factor-related peptides.

PubMed ID: 18052377

DOI: 10.1021/ja0760933

PubMed ID: 20966082

Title: Structural basis for hormone recognition by the Human CRFR2{alpha} G protein-coupled receptor.

PubMed ID: 20966082

DOI: 10.1074/jbc.m110.186072

Sequence Information:

  • Length: 161
  • Mass: 17961
  • Checksum: B83B3D8D30879911
  • Sequence:
    • MLMPVHFLLL LLLLLGGPRT GLPHKFYKAK PIFSCLNTAL SEAEKGQWED ASLLSKRSFH 
YLRSRDASSG EEEEGKEKKT FPISGARGGA RGTRYRYVSQ AQPRGKPRQD TAKSPHRTKF 
TLSLDVPTNI MNLLFNIAKA KNLRAQAAAN AHLMAQIGRK K