Details for: NKX2 2

Gene ID: 4821

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: NKX2 2

Ensembl ID: ENSG00000125820

Description: NK2 homeobox 2

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

  • Developmental biology
    (R-HSA-1266738)
  • Regulation of beta-cell development
    (R-HSA-186712)
  • Regulation of gene expression in beta cells
    (R-HSA-210745)
  • Regulation of gene expression in endocrine-committed (neurog3+) progenitor cells
    (R-HSA-210746)
  • Astrocyte differentiation
    (GO:0048708)
  • Brain development
    (GO:0007420)
  • Cell differentiation
    (GO:0030154)
  • Chromatin
    (GO:0000785)
  • Cis-regulatory region sequence-specific dna binding
    (GO:0000987)
  • Digestive tract development
    (GO:0048565)
  • Dna-binding transcription activator activity, rna polymerase ii-specific
    (GO:0001228)
  • Dna-binding transcription factor activity, rna polymerase ii-specific
    (GO:0000981)
  • Negative regulation of neuron differentiation
    (GO:0045665)
  • Neuroendocrine cell differentiation
    (GO:0061101)
  • Neuron fate specification
    (GO:0048665)
  • Nucleoplasm
    (GO:0005654)
  • Nucleus
    (GO:0005634)
  • Oligodendrocyte development
    (GO:0014003)
  • Optic nerve development
    (GO:0021554)
  • Pancreatic a cell fate commitment
    (GO:0003326)
  • Pancreatic pp cell fate commitment
    (GO:0003329)
  • Positive regulation of epithelial cell differentiation
    (GO:0030858)
  • Positive regulation of gene expression
    (GO:0010628)
  • Positive regulation of neuron differentiation
    (GO:0045666)
  • Positive regulation of oligodendrocyte differentiation
    (GO:0048714)
  • Positive regulation of transcription by rna polymerase ii
    (GO:0045944)
  • Protein binding
    (GO:0005515)
  • Regulation of transcription by rna polymerase ii
    (GO:0006357)
  • Response to glucose
    (GO:0009749)
  • Response to progesterone
    (GO:0032570)
  • Rna polymerase ii cis-regulatory region sequence-specific dna binding
    (GO:0000978)
  • Smoothened signaling pathway
    (GO:0007224)
  • Spinal cord motor neuron differentiation
    (GO:0021522)
  • Spinal cord oligodendrocyte cell fate specification
    (GO:0021530)
  • Type b pancreatic cell development
    (GO:0003323)
  • Type b pancreatic cell fate commitment
    (GO:0003327)
  • Ventral spinal cord interneuron fate determination
    (GO:0060580)

Significant Cells

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

  • pancreatic D cell CL0000173
    CSI 17.19
    rCSI 16.91%
    PRS 91.26
  • enteroendocrine cell CL0000164
    CSI 14.19
    rCSI 19.39%
    PRS 88.16
  • astrocyte of the cerebral cortex CL0002605
    CSI 12.12
    rCSI 27.17%
    PRS 76.47
  • pancreatic A cell CL0000171
    CSI 11.29
    rCSI 11.83%
    PRS 91.56
  • P/D1 enteroendocrine cell CL0002268
    CSI 9.49
    rCSI 51.65%
    PRS 92.07
  • type B pancreatic cell CL0000169
    CSI 8.84
    rCSI 19.56%
    PRS 89.43
  • type L enteroendocrine cell CL0002279
    CSI 8.3
    rCSI 15.57%
    PRS 91.73
  • pancreatic PP cell CL0002275
    CSI 8.29
    rCSI 33.01%
    PRS 93.03
  • type EC enteroendocrine cell CL0000577
    CSI 7.72
    rCSI 27.4%
    PRS 90.9
  • enteroendocrine cell of colon CL0009042
    CSI 5.99
    rCSI 28.07%
    PRS 92.08
  • differentiation-committed oligodendrocyte precursor CL4023059
    CSI 3.8
    rCSI 6.91%
    PRS 83.14
  • Bergmann glial cell CL0000644
    CSI 2.82
    rCSI 3.86%
    PRS 81.93
  • pancreatic epsilon cell CL0005019
    CSI 2.01
    rCSI 9.38%
    PRS 93.13
  • neuroendocrine cell CL0000165
    CSI 1.94
    rCSI 7.5%
    PRS 92.89
  • enteroendocrine cell of small intestine CL0009006
    CSI 1.04
    rCSI 2.29%
    PRS 92.77

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.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • 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 [NKX2 2](/details-gene/4821) is a protein-coding gene located on chromosome 20 that encodes the homeobox protein Nkx-2.2, a DNA-binding transcription factor. This protein plays a fundamental role in developmental processes, particularly in the differentiation and fate specification of cells within the pancreas and the central nervous system. Expression data reveals its high significance in various endocrine cell lineages, including pancreatic islet cells such as [pancreatic D cell](/details-cell/CL0000173)s and [type B pancreatic cell](/details-cell/CL0000169)s, as well as [enteroendocrine cell](/details-cell/CL0000164)s of the digestive tract. Concurrently, it is a key marker for glial cell development, with notable expression in [astrocyte of the cerebral cortex](/details-cell/CL0002605) and oligodendrocyte precursors. Its function is primarily executed within the [nucleus](/details-cell/GO:0005634), where it regulates the transcription of target genes essential for cell differentiation and identity. ## Cellular Roles and Expression Landscape The expression profile of [NKX2 2](/details-gene/4821) underscores its specialized function as a key regulator in neuroendocrine and glial lineages. **Overall**, the gene shows the highest significance in cells responsible for hormone production within the digestive system. It is a defining marker for [pancreatic D cell](/details-cell/CL0000173) (CSI: 17.19), [enteroendocrine cell](/details-cell/CL0000164) (CSI: 14.19), [pancreatic A cell](/details-cell/CL0000171) (CSI: 11.29), and [type B pancreatic cell](/details-cell/CL0000169) (CSI: 8.84). This consistent, high-level expression across multiple pancreatic and intestinal endocrine cell types suggests a conserved role in establishing and maintaining the transcriptional programs of the diffuse neuroendocrine system. In parallel, [NKX2 2](/details-gene/4821) is integral to the development of the central nervous system, particularly in glial cell differentiation. It is highly significant in [astrocyte of the cerebral cortex](/details-cell/CL0002605) (CSI: 12.12) and also marks [differentiation-committed oligodendrocyte precursor](/details-cell/CL4023059)s (CSI: 3.80). This dual role in both pancreatic and neural development is a common feature of transcription factors involved in cell fate specification during embryogenesis. The data collectively positions [NKX2 2](/details-gene/4821) as a critical transcription factor for the maturation of both hormone-secreting endocrine cells and supportive glial cells. ## Pathways and Molecular Function Functionally, [NKX2 2](/details-gene/4821) operates as a DNA-binding transcription factor, as annotated by its molecular function in [dna-binding transcription factor activity, rna polymerase ii-specific](/details-cell/GO:0000981) and its localization to the [nucleus](/details-cell/GO:0005634) and [chromatin](/details-cell/GO:0000785). Its primary biological role involves the regulation of gene expression to control cell differentiation pathways. This is strongly supported by its association with numerous developmental processes. In the pancreas, it is implicated in the fate commitment of multiple islet cells, including [pancreatic a cell fate commitment](/details-cell/GO:0003326), [type b pancreatic cell fate commitment](/details-cell/GO:0003327), and [pancreatic pp cell fate commitment](/details-cell/GO:0003329). This is further substantiated by its role in Reactome pathways such as [Regulation of beta-cell development](/details-reactome/R-HSA-186712) and [Regulation of gene expression in beta cells](/details-reactome/R-HSA-210745). This involvement is consistent with its high expression in mature pancreatic cell types. In the nervous system, its function is highlighted by involvement in [astrocyte differentiation](/details-cell/GO:0048708), [oligodendrocyte development](/details-cell/GO:0014003), and [spinal cord motor neuron differentiation](/details-cell/GO:0021522). These annotated functions align perfectly with its observed high significance in astrocytes and oligodendrocyte precursors, solidifying its role as a key regulator of glial and neuronal cell specification. ## Research Directions The specific and high-level expression of [NKX2 2](/details-gene/4821) in pancreatic endocrine cells and developing glial cells provides a foundation for several research avenues, particularly concerning metabolic diseases and neurodevelopmental or degenerative disorders. While one study found that mutations in the coding region were not associated with maturity-onset diabetes of the young (MODY) in a Japanese cohort ([Link](https://doi.org/10.2337/diab.47.8.1356)), its critical role in beta-cell development suggests its regulatory regions or downstream pathways could still be relevant to diabetes pathophysiology. Based on its established roles, several testable hypotheses can be proposed: 1. Misexpression or mutation of [NKX2 2](/details-gene/4821) impairs the terminal differentiation of oligodendrocyte precursor cells, leading to defective myelination and contributing to the pathology of demyelinating diseases such as multiple sclerosis. 2. As a key transcription factor in multiple hormone-producing cell types, [NKX2 2](/details-gene/4821) acts as a terminal selector gene that directly activates and maintains the expression of hormone-processing enzymes and secretion machinery common to both pancreatic islets and enteroendocrine cells. A compelling experiment to test the second hypothesis would be to use an in vitro organoid system. CRISPR-Cas9-mediated knockout of [NKX2 2](/details-gene/4821) could be performed in human pluripotent stem cells, which are then differentiated towards pancreatic islet or intestinal organoid fates. Subsequent single-cell multi-omics (e.g., scRNA-seq and scATAC-seq) would reveal the direct transcriptional targets of [NKX2 2](/details-gene/4821) and determine if its absence leads to a failure in endocrine cell specification and a collapse of the mature endocrine cell gene regulatory network. Therapeutically, [NKX2 2](/details-gene/4821) itself is a challenging drug target due to its nature as a transcription factor. However, its role in cell fate specification makes it a highly valuable tool for regenerative medicine. Overexpression or controlled activation of [NKX2 2](/details-gene/4821), in combination with other key transcription factors, could be a cornerstone of protocols for generating functional, glucose-responsive [type B pancreatic cell](/details-cell/CL0000169)s from stem cells for cell-based therapies for Type 1 diabetes. This represents a strategy of targeted activation or gene delivery rather than small molecule inhibition.

Genular Protein ID: 1435449841

Symbol: NKX22_HUMAN

Name: Homeobox protein Nkx-2.2

UniProtKB Accession Codes:

O95096

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 5 Ensembl 1 GO 31 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRINTS 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 RNAct 1 Reactome 2 RefSeq 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 9703340

Title: Beta-cell transcription factors and diabetes: mutations in the coding region of the BETA2/NeuroD1 (NEUROD1) and Nkx2.2 (NKX2B) genes are not associated with maturity-onset diabetes of the young in Japanese.

PubMed ID: 9703340

DOI: 10.2337/diab.47.8.1356

PubMed ID: 11780052

Title: The DNA sequence and comparative analysis of human chromosome 20.

PubMed ID: 11780052

DOI: 10.1038/414865a

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

Sequence Information:

  • Length: 273
  • Mass: 30133
  • Checksum: 91BDA220BAFA63D1
  • Sequence:
    • MSLTNTKTGF SVKDILDLPD TNDEEGSVAE GPEEENEGPE PAKRAGPLGQ GALDAVQSLP 
LKNPFYDSSD NPYTRWLAST EGLQYSLHGL AAGAPPQDSS SKSPEPSADE SPDNDKETPG 
GGGDAGKKRK RRVLFSKAQT YELERRFRQQ RYLSAPEREH LASLIRLTPT QVKIWFQNHR 
YKMKRARAEK GMEVTPLPSP RRVAVPVLVR DGKPCHALKA QDLAAATFQA GIPFSAYSAQ 
SLQHMQYNAQ YSSASTPQYP TAHPLVQAQQ WTW