Details for: PHOX2B

Gene ID: 8929

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: PHOX2B

Ensembl ID: ENSG00000109132

Description: paired like homeobox 2B

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

  • Autonomic nervous system development
    (GO:0048483)
  • Brainstem development
    (GO:0003360)
  • Cell differentiation in hindbrain
    (GO:0021533)
  • Cellular response to bmp stimulus
    (GO:0071773)
  • Cellular response to carbon dioxide
    (GO:0071244)
  • Chromatin
    (GO:0000785)
  • Dna-binding transcription activator activity, rna polymerase ii-specific
    (GO:0001228)
  • Dna-binding transcription factor activity, rna polymerase ii-specific
    (GO:0000981)
  • Dopaminergic neuron differentiation
    (GO:0071542)
  • Efferent axon development in a lateral line nerve
    (GO:0048894)
  • Enteric nervous system development
    (GO:0048484)
  • Glial cell differentiation
    (GO:0010001)
  • Hindbrain tangential cell migration
    (GO:0021934)
  • Inner ear development
    (GO:0048839)
  • Medullary reticular formation development
    (GO:0021723)
  • Membrane depolarization
    (GO:0051899)
  • Motor neuron migration
    (GO:0097475)
  • Negative regulation of neuron differentiation
    (GO:0045665)
  • Negative regulation of type b pancreatic cell proliferation
    (GO:1904691)
  • Neural crest cell migration involved in autonomic nervous system development
    (GO:1901166)
  • Neuron migration
    (GO:0001764)
  • Noradrenergic neuron development
    (GO:0003358)
  • Noradrenergic neuron differentiation
    (GO:0003357)
  • Nucleoplasm
    (GO:0005654)
  • Parasympathetic nervous system development
    (GO:0048486)
  • Positive regulation of cold-induced thermogenesis
    (GO:0120162)
  • Positive regulation of g2/m transition of mitotic cell cycle
    (GO:0010971)
  • Positive regulation of neuron differentiation
    (GO:0045666)
  • Positive regulation of transcription by rna polymerase ii
    (GO:0045944)
  • Regulation of gene expression
    (GO:0010468)
  • Regulation of respiratory gaseous exchange by nervous system process
    (GO:0002087)
  • Regulation of transcription by rna polymerase ii
    (GO:0006357)
  • Respiratory system development
    (GO:0060541)
  • Response to activity
    (GO:0014823)
  • Retrotrapezoid nucleus neuron differentiation
    (GO:0061452)
  • Rna polymerase ii cis-regulatory region sequence-specific dna binding
    (GO:0000978)
  • Rna polymerase ii transcription regulatory region sequence-specific dna binding
    (GO:0000977)
  • Sequence-specific double-stranded dna binding
    (GO:1990837)
  • Skeletal muscle cell differentiation
    (GO:0035914)
  • Sympathetic ganglion development
    (GO:0061549)
  • Sympathetic nervous system development
    (GO:0048485)
  • Type b pancreatic cell proliferation
    (GO:0044342)

Significant Cells

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

  • peripheral nervous system neuron CL2000032
    CSI 9.56
    rCSI 13.03%
    PRS 100
  • neural crest cell CL0011012
    CSI 8.46
    rCSI 6.69%
    PRS 100
  • glial cell CL0000125
    CSI 6.64
    rCSI 25.29%
    PRS 99.91
  • neural cell CL0002319
    CSI 5.43
    rCSI 20.49%
    PRS 100
  • enteric neuron CL0007011
    CSI 1.73
    rCSI 25.63%
    PRS 100

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 [PHOX2B](/details-gene/8929) is a protein-coding gene that encodes the paired-like homeobox 2B transcription factor. This protein is a critical regulator of neuronal development, particularly within the autonomic nervous system. Expression data indicates that [PHOX2B](/details-gene/8929) is a highly significant marker for cell types such as the [peripheral nervous system neuron](/details-cell/CL2000032) and its progenitor, the [neural crest cell](/details-cell/CL0011012). Functionally, it orchestrates the differentiation and migration of various neural lineages, including enteric and noradrenergic neurons. Clinically, mutations in [PHOX2B](/details-gene/8929) are causally linked to severe congenital disorders, most notably congenital central hypoventilation syndrome (CCHS) ([12640453](https://doi.org/10.1038/ng1130)) and are also implicated in the pathogenesis of neuroblastoma ([15024693](https://doi.org/10.1086/383253)), a pediatric cancer of the sympathetic nervous system. The OMIM database lists its association with CCHS under entry [209880](https://omim.org/entry/209880). ## Cellular Roles and Expression Landscape The expression profile of [PHOX2B](/details-gene/8929) highlights its specialized role as a master regulator in the developing nervous system. **Overall**, its significance is highest in the [peripheral nervous system neuron](/details-cell/CL2000032) (CSI: 9.56) and the multipotent [neural crest cell](/details-cell/CL0011012) (CSI: 8.46) from which many peripheral neurons arise. This is complemented by significant scores in [glial cell](/details-cell/CL0000125) (CSI: 6.64), [neural cell](/details-cell/CL0002319) (CSI: 5.43), and the more specialized [enteric neuron](/details-cell/CL0007011) (CSI: 1.73). This pattern of expression is consistent with a fundamental role in establishing the identity and function of the autonomic nervous system. Its high significance in [neural crest cell](/details-cell/CL0011012)s underscores its early role in lineage commitment for sympathetic, parasympathetic, and enteric ganglia. The strong and specific expression signature suggests that [PHOX2B](/details-gene/8929) activity is tightly restricted to these neural lineages, acting as a key determinant of their developmental fate. ## Pathways and Molecular Function As a transcription factor, the molecular function of [PHOX2B](/details-gene/8929) is centered on its ability to bind DNA and regulate gene expression ([GO:0000978](https://www.ebi.ac.uk/QuickGO/term/GO:0000978), [GO:0001228](https://www.ebi.ac.uk/QuickGO/term/GO:0001228)). It is localized to the [nucleoplasm](/details-cell/GO0005654) and [chromatin](/details-cell/GO0000785), where it activates transcription from target gene promoters. The biological processes associated with [PHOX2B](/details-gene/8929) align precisely with its cellular expression profile. It is a key participant in 'autonomic nervous system development' ([GO:0048483](https://www.ebi.ac.uk/QuickGO/term/GO:0048483)), 'enteric nervous system development' ([GO:0048484](https://www.ebi.ac.uk/QuickGO/term/GO:0048484)), and 'noradrenergic neuron differentiation' ([GO:0003357](https://www.ebi.ac.uk/QuickGO/term/GO:0003357)). This latter function is critical for the development of the sympathetic nervous system and is consistent with its implication in neuroblastoma, a tumor of this lineage ([Link](https://doi.org/10.1086/383253)). Critically, its involvement in the 'regulation of respiratory gaseous exchange by nervous system process' ([GO:0002087](https://www.ebi.ac.uk/QuickGO/term/GO:0002087)) and 'cellular response to carbon dioxide' ([GO:0071244](https://www.ebi.ac.uk/QuickGO/term/GO:0071244)) provides a direct molecular link to the pathophysiology of congenital central hypoventilation syndrome ([Link](https://doi.org/10.1007/s00439-003-1036-z)). ## Research Directions The central role of [PHOX2B](/details-gene/8929) in both normal neural development and disease presents several avenues for future research. **Proposed Hypotheses:** 1. Given that germline mutations in [PHOX2B](/details-gene/8929) predispose individuals to neuroblastoma ([Link](https://doi.org/10.1086/428366)), it is hypothesized that these mutations disrupt the delicate balance between differentiation and proliferation in [neural crest cell](/details-cell/CL0011012) derivatives. The mutant protein may fail to activate key differentiation genes while simultaneously permitting the expression of pro-proliferative targets, locking sympathoadrenal progenitors in an oncogenic state. 2. In the context of congenital central hypoventilation syndrome, it is hypothesized that CCHS-associated [PHOX2B](/details-gene/8929) mutations specifically disable the transcriptional network within brainstem neurons that confers sensitivity to hypercapnia. This leads to a failure of these neurons to activate the appropriate respiratory drive in response to elevated blood CO2 levels. **Experimental Approach:** To test the second hypothesis, one could employ a human induced pluripotent stem cell (iPSC)-based model. iPSCs derived from CCHS patients and healthy controls could be differentiated into retrotrapezoid nucleus-like neurons, a key CO2-sensing population where [PHOX2B](/details-gene/8929) is active. By performing single-cell RNA-sequencing and functional assays (e.g., calcium imaging) on these neuronal cultures under normocapnic versus hypercapnic conditions, it would be possible to directly identify the downstream target genes regulated by [PHOX2B](/details-gene/8929) that fail to respond to CO2 in diseased cells, thereby elucidating the molecular basis of the hypoventilation phenotype. **Therapeutic Potential:** Directly targeting a transcription factor like [PHOX2B](/details-gene/8929) is challenging. In neuroblastoma, where its function is co-opted for tumor maintenance, an indirect therapeutic strategy involving the inhibition of its critical downstream effectors or upstream regulators could be more feasible. For CCHS, a developmental disorder caused by haploinsufficiency, the goal would be functional restoration rather than inhibition. Future therapeutic avenues may lie in gene therapy or novel molecular strategies aimed at correcting the function of the mutated allele or augmenting the output from the remaining healthy allele in affected neurons.

Genular Protein ID: 411743358

Symbol: PHX2B_HUMAN

Name: Paired mesoderm homeobox protein 2B

UniProtKB Accession Codes:

Q99453 Q6PJD9

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 DMDM 1 DNASU 1 DisGeNET 1 EMBL 4 Ensembl 1 GO 42 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 5 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 4 OrthoDB 1 PANTHER 2 PDB 5 PDBsum 5 PIR 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 RefSeq 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9039501

Title: Identification and cloning of neuroblastoma-specific and nerve tissue-specific genes through compiled expression profiles.

PubMed ID: 9039501

DOI: 10.1093/dnares/3.5.311

PubMed ID: 11034547

Title: Paired-like homeodomain proteins Phox2a/Arix and Phox2b/NBPhox have similar genetic organization and independently regulate dopamine beta-hydroxylase gene transcription.

PubMed ID: 11034547

DOI: 10.1089/104454900439773

PubMed ID: 10395798

Title: Genomic structure and functional characterization of NBPhox (PMX2B), a homeodomain protein specific to catecholaminergic cells that is involved in second messenger-mediated transcriptional activation.

PubMed ID: 10395798

DOI: 10.1006/geno.1999.5845

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: 14566559

Title: Molecular analysis of congenital central hypoventilation syndrome.

PubMed ID: 14566559

DOI: 10.1007/s00439-003-1036-z

PubMed ID: 12640453

Title: Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.

PubMed ID: 12640453

DOI: 10.1038/ng1130

PubMed ID: 15024693

Title: Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.

PubMed ID: 15024693

DOI: 10.1086/383253

PubMed ID: 15657873

Title: PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.

PubMed ID: 15657873

DOI: 10.1086/428366

PubMed ID: 16691592

Title: PHOX2B analysis in non-syndromic neuroblastoma cases shows novel mutations and genotype-phenotype associations.

PubMed ID: 16691592

DOI: 10.1002/ajmg.a.31278

Sequence Information:

  • Length: 314
  • Mass: 31621
  • Checksum: 40737F71948B595A
  • Sequence:
    • MYKMEYSYLN SSAYESCMAG MDTSSLASAY ADFSSCSQAS GFQYNPIRTT FGATSGCPSL 
TPGSCSLGTL RDHQSSPYAA VPYKLFTDHG GLNEKRKQRR IRTTFTSAQL KELERVFAET 
HYPDIYTREE LALKIDLTEA RVQVWFQNRR AKFRKQERAA AAAAAAAKNG SSGKKSDSSR 
DDESKEAKST DPDSTGGPGP NPNPTPSCGA NGGGGGGPSP AGAPGAAGPG GPGGEPGKGG 
AAAAAAAAAA AAAAAAAAAA GGLAAAGGPG QGWAPGPGPI TSIPDSLGGP FASVLSSLQR 
PNGAKAALVK SSMF