Details for: NKX2 1

Gene ID: 7080

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 1

Ensembl ID: ENSG00000136352

Description: NK2 homeobox 1

Cell Significance Landscape

Associated with

Significant Cells

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

  • epithelial cell of lung CL0000082
    CSI 7.19
    rCSI 5.96%
    PRS 99.27
  • epithelial cell of lower respiratory tract CL0002632
    CSI 6.91
    rCSI 5.36%
    PRS 99.37
  • lung ciliated cell CL1000271
    CSI 6.28
    rCSI 7.26%
    PRS 97.11
  • epithelial cell CL0000066
    CSI 4.88
    rCSI 7.5%
    PRS 94.31
  • lung neuroendocrine cell CL1000223
    CSI 4.8
    rCSI 7.1%
    PRS 98.21
  • pulmonary alveolar type 2 cell CL0002063
    CSI 4.11
    rCSI 6.38%
    PRS 98.68
  • lung secretory cell CL1000272
    CSI 3.39
    rCSI 8.39%
    PRS 99.26
  • respiratory basal cell CL0002633
    CSI 3.05
    rCSI 3.16%
    PRS 99.05
  • respiratory suprabasal cell CL4033048
    CSI 2.85
    rCSI 3.65%
    PRS 99.16
  • multi-ciliated epithelial cell CL0005012
    CSI 2.74
    rCSI 2.73%
    PRS 96.95
  • ependymal cell CL0000065
    CSI 2.71
    rCSI 5.5%
    PRS 92.86
  • airway submucosal gland duct basal cell CL4033024
    CSI 2.01
    rCSI 12.84%
    PRS 99
  • pulmonary alveolar type 1 cell CL0002062
    CSI 1.47
    rCSI 8.46%
    PRS 97.83
  • ciliated columnar cell of tracheobronchial tree CL0002145
    CSI 1.31
    rCSI 2.99%
    PRS 95.93

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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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 1](/details-gene/7080) (NK2 homeobox 1), also known as Thyroid Transcription Factor 1 (TTF-1), is a protein-coding gene located on chromosome 14q13.3. It encodes a DNA-binding transcription factor that plays a pivotal role in the morphogenesis and development of the lung, thyroid, and specific regions of the forebrain. Consistent with its developmental functions, its expression is highly significant in various lung epithelial cell types, including [epithelial cell of lung](/details-cell/CL0000082) and [pulmonary alveolar type 2 cell](/details-cell/CL0002063). Functionally, [NKX2 1](/details-gene/7080) is involved in regulating gene expression critical for cell differentiation and organogenesis. Clinically, mutations in this gene are associated with a spectrum of disorders known as brain-thyroid-lung syndrome, which can include congenital hypothyroidism, respiratory distress, and benign hereditary chorea ([118700](https://omim.org/entry/118700), [600635](https://omim.org/entry/600635)). ## Cellular Roles and Expression Landscape The expression profile of [NKX2 1](/details-gene/7080) underscores its role as a master regulator of epithelial identity, particularly within the respiratory system. **Overall**, the gene shows its highest significance in a broad range of lung epithelial cells. It is a top marker for [epithelial cell of lung](/details-cell/CL0000082) (CSI: 7.19), [epithelial cell of lower respiratory tract](/details-cell/CL0002632) (CSI: 6.91), and [lung ciliated cell](/details-cell/CL1000271) (CSI: 6.28). Its high significance extends to specialized lung cell types crucial for gas exchange and surfactant production, such as [pulmonary alveolar type 2 cell](/details-cell/CL0002063) (CSI: 4.11) and [pulmonary alveolar type 1 cell](/details-cell/CL0002062) (CSI: 1.47), as well as progenitor-like [respiratory basal cell](/details-cell/CL0002633) (CSI: 3.05). This pattern suggests that [NKX2 1](/details-gene/7080) is not only essential for the initial development of the lung but also for the maintenance and function of its diverse epithelial lineages. Beyond the lung, the gene's significance in [ependymal cell](/details-cell/CL0000065) (CSI: 2.71) is consistent with its established role in brain development. This expression highlights its pleiotropic effects, governing distinct developmental programs in different organ systems. ## Pathways and Molecular Function As a transcription factor, [NKX2 1](/details-gene/7080) primarily functions within the [nucleus](/details-cell/GO:0005634), where it binds to DNA to regulate gene expression. Its molecular function is defined by its [DNA-binding transcription factor activity, rna polymerase ii-specific](/details-cell/GO:0000981), enabling it to act as both an activator and a repressor of transcription. The biological processes associated with [NKX2 1](/details-gene/7080) are heavily concentrated on organogenesis and cell fate determination. Key annotated functions include: * **Organ Development:** It is indispensable for [lung development](/details-cell/GO:0030324), [thyroid gland development](/details-cell/GO:0030878), and [forebrain development](/details-cell/GO:0030900), which aligns with the clinical phenotypes observed in patients with [NKX2 1](/details-gene/7080) mutations ([Link](https://doi.org/10.1172/jci14341)). * **Cell Differentiation:** The gene directs the differentiation of multiple specialized cell types, including [type ii pneumocyte differentiation](/details-cell/GO:0060510) and [cerebral cortex gabaergic interneuron differentiation](/details-cell/GO:0021892). This role is critical for establishing the mature cellular architecture of the lung and brain. * **Transcriptional Regulation:** [NKX2 1](/details-gene/7080) engages in both [positive regulation of dna-templated transcription](/details-cell/GO:0045893) and [negative regulation of dna-templated transcription](/details-cell/GO:0045892), indicating a sophisticated, context-dependent role in controlling gene networks. For instance, it has been shown to interact with coactivators to regulate thyroid differentiation ([Link](https://doi.org/10.1016/j.yexcr.2008.10.016)). * **Neural Processes:** Its involvement in [axon guidance](/details-cell/GO:0007411) and [cerebral cortex cell migration](/details-cell/GO:0021795) provides a molecular basis for the neurological defects, such as chorea, associated with its haploinsufficiency ([Link](https://doi.org/10.1093/hmg/11.8.971)). ## Research Directions The well-defined role of [NKX2 1](/details-gene/7080) in development and its association with brain-thyroid-lung syndrome provide a strong foundation for further investigation into its function in health and disease. **Proposed Hypotheses:** 1. Given its high significance in both progenitor and terminally differentiated lung epithelial cells, we hypothesize that **[NKX2 1](/details-gene/7080) functions as a lineage-survival factor whose expression level dictates the balance between cell self-renewal and differentiation in the lung epithelium.** A reduction in its dosage may predispose individuals to respiratory distress by impairing the regenerative capacity of basal cells and the function of alveolar cells. 2. Based on its role in interneuron differentiation and the neurological symptoms of its deficiency, we hypothesize that **haploinsufficiency of [NKX2 1](/details-gene/7080) specifically disrupts the maturation and synaptic integration of striatal interneurons, leading to the disinhibition of motor circuits that manifests as benign hereditary chorea.** This is supported by studies linking mutations to neurological defects ([Link](https://doi.org/10.1172/jci14192)). **Key Experimental Approach:** To test the first hypothesis regarding its role in lung epithelial lineage maintenance, one could employ a human lung organoid model derived from induced pluripotent stem cells (iPSCs). * **Methodology:** Using CRISPR-Cas9, create isogenic iPSC lines with heterozygous (simulating haploinsufficiency) and homozygous knockout of [NKX2 1](/details-gene/7080). Differentiate these lines, alongside a wild-type control, into mature lung organoids. * **Analysis:** Perform single-cell RNA sequencing at different time points during differentiation to map the developmental trajectories and identify cell fate decision points that are disrupted by [NKX2 1](/details-gene/7080) deficiency. Quantitative immunofluorescence for markers of basal cells (e.g., KRT5), alveolar type 1 cells (e.g., AGER), and alveolar type 2 cells (e.g., SFTPC) would be used to assess changes in cellular composition and organoid structure. **Therapeutic Potential:** As a transcription factor, [NKX2 1](/details-gene/7080) is a challenging direct drug target. However, its roles in disease suggest several therapeutic avenues. In lung adenocarcinoma, where it acts as a lineage-survival oncogene, the therapeutic strategy would be **inhibition**. This could be achieved indirectly by targeting its critical downstream effectors or protein co-factors. For the haploinsufficiency syndromes (e.g., brain-thyroid-lung syndrome), a strategy of **activation** would be needed. This is more difficult but could potentially involve small molecules that stabilize the [NKX2 1](/details-gene/7080) protein or enhance the transcriptional output from the remaining functional allele.

Genular Protein ID: 22978039

Symbol: NKX21_HUMAN

Name: Homeobox protein Nkx-2.1

UniProtKB Accession Codes:

P43699 D3DSA3 O14954 O14955 Q7KZF6 Q9BRJ8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CTD 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 13 Ensembl 4 GO 53 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 7 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 4 OrthoDB 1 PANTHER 2 PIR 1 PRINTS 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 RefSeq 2 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: 7711079

Title: The complete nucleotide sequence of the mouse thyroid-specific enhancer-binding protein (T/EBP) gene: extensive identity of the deduced amino acid sequence with the human protein.

PubMed ID: 7711079

DOI: 10.1016/0167-4781(95)00033-d

PubMed ID: 7711080

Title: Cloning and sequence analysis of human thyroid transcription factor 1.

PubMed ID: 7711080

DOI: 10.1016/0167-4781(95)00034-e

PubMed ID: 7713914

Title: Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells.

PubMed ID: 7713914

DOI: 10.1074/jbc.270.14.8108

PubMed ID: 9545595

Title: Structure of the human Nkx2.1 gene.

PubMed ID: 9545595

DOI: 10.1016/s0167-4781(97)00210-8

PubMed ID: 12508121

Title: The DNA sequence and analysis of human chromosome 14.

PubMed ID: 12508121

DOI: 10.1038/nature01348

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: 19010321

Title: TAZ is a coactivator for Pax8 and TTF-1, two transcription factors involved in thyroid differentiation.

PubMed ID: 19010321

DOI: 10.1016/j.yexcr.2008.10.016

PubMed ID: 19176457

Title: A germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma.

PubMed ID: 19176457

DOI: 10.1093/jnci/djn471

PubMed ID: 11971878

Title: Mutations in TITF-1 are associated with benign hereditary chorea.

PubMed ID: 11971878

DOI: 10.1093/hmg/11.8.971

PubMed ID: 11854318

Title: Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice.

PubMed ID: 11854318

DOI: 10.1172/jci14192

PubMed ID: 11854319

Title: Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency.

PubMed ID: 11854319

DOI: 10.1172/jci14341

PubMed ID: 15289765

Title: Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1.

PubMed ID: 15289765

DOI: 10.1016/j.jpeds.2004.04.011

PubMed ID: 15955952

Title: A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa.

PubMed ID: 15955952

DOI: 10.1212/01.wnl.0000164000.75046.cc

PubMed ID: 24453141

Title: A novel mutation of NKX2-1 affecting 2 generations with hypothyroidism and choreoathetosis: part of the spectrum of brain-thyroid-lung syndrome.

PubMed ID: 24453141

DOI: 10.1177/0883073813518243

PubMed ID: 24714694

Title: Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum.

PubMed ID: 24714694

DOI: 10.1136/jmedgenet-2013-102248

PubMed ID: 26723978

Title: Functional characterization of two novel mutations in TTF-1/NKX2.1 homeodomain in patients with benign hereditary chorea.

PubMed ID: 26723978

DOI: 10.1016/j.jns.2015.11.050

Sequence Information:

  • Length: 371
  • Mass: 38596
  • Checksum: 5F1E3B40A1BBD862
  • Sequence:
    • MSMSPKHTTP FSVSDILSPL EESYKKVGME GGGLGAPLAA YRQGQAAPPT AAMQQHAVGH 
HGAVTAAYHM TAAGVPQLSH SAVGGYCNGN LGNMSELPPY QDTMRNSASG PGWYGANPDP 
RFPAISRFMG PASGMNMSGM GGLGSLGDVS KNMAPLPSAP RRKRRVLFSQ AQVYELERRF 
KQQKYLSAPE REHLASMIHL TPTQVKIWFQ NHRYKMKRQA KDKAAQQQLQ QDSGGGGGGG 
GTGCPQQQQA QQQSPRRVAV PVLVKDGKPC QAGAPAPGAA SLQGHAQQQA QHQAQAAQAA 
AAAISVGSGG AGLGAHPGHQ PGSAGQSPDL AHHAASPAAL QGQVSSLSHL NSSGSDYGTM 
SCSTLLYGRT W