Affinage

PHOX2B

Paired mesoderm homeobox protein 2B · UniProt Q99453

Length
314 aa
Mass
31.6 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PHOX2B is a paired-like homeodomain transcription factor that acts as a master regulator of autonomic nervous system development, required for the formation of all autonomic ganglia, three cranial sensory ganglia, branchial/visceral motor neurons, and all central and peripheral noradrenergic centers including the locus coeruleus (PMID:10360575, PMID:10704382, PMID:10736201). It drives neuronal progenitor cell cycle exit and post-mitotic differentiation, controlling proneural and patterning genes (inducing Ngn2, Mash1, Islet1, Nkx6.1/Nkx6.2 while repressing Hes5, Id2, Pax6, Olig2) to specify a generic neuronal and visceral motor program (PMID:11060244, PMID:12399315). Mechanistically, PHOX2B binds homeodomain recognition sites in the promoters of noradrenergic and autonomic identity genes — directly activating DBH, PHOX2A, TLX2, ALK, and RET, and autoregulating its own transcription through four sites in its proximal promoter (PMID:9798905, PMID:11549713, PMID:16144830, PMID:16402914, PMID:20957039, PMID:19853745). PHOX2B functions combinatorially, cooperating with Sox10 and Nkx2-1 at RET, with Mash1 at RGS4, with Hand2 in proliferation control, and forming homodimers and PHOX2A heterodimers via its homeodomain; it is itself a transcriptional target of Hox/Pbx/Meis and Nkx2.2 inputs and is potentiated by the interacting partner Trim11 (PMID:14627646, PMID:15289435, PMID:18275850, PMID:19853745, PMID:20089899, PMID:27129232). At the circuit level, PHOX2B specifies retrotrapezoid nucleus and nucleus tractus solitarius neurons that confer intrinsic CO2/H+ chemosensitivity and drive breathing automaticity through glutamatergic projections to respiratory centers (PMID:18198276, PMID:25866925, PMID:28488367, PMID:30626698). PHOX2B mutations cause autonomic disease through distinct mechanisms: polyalanine expansions produce length-dependent loss of DNA binding, transcriptional activity, nuclear import, and cytoplasmic aggregation that can sequester wild-type protein, whereas frameshift and nonpolyalanine mutations act through dominant-negative and gain-of-function effects, including conversion of a Sox10 enhancer from repression to activation (PMID:16249188, PMID:15888479, PMID:22922260, PMID:23103552, PMID:27129232).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 Medium

    Established that Phox2b and the paralog Phox2a are co-regulated, placing Phox2b within a cross-regulatory homeodomain network in autonomic and cranial motor neurons before its molecular targets were known.

    Evidence In situ hybridization and immunostaining in wild-type and Phox2a knockout mouse embryos

    PMID:9374403

    Open questions at the time
    • Did not establish direct DNA binding or transactivation between the paralogs
    • Did not define the molecular targets specifying autonomic identity
  2. 1999 High

    Defined Phox2b as essential for the formation of all autonomic ganglia and for the noradrenergic biosynthetic program, establishing it as a genetic master regulator rather than a modifier.

    Evidence Targeted gene knockout in mice with analysis of ganglionic development and Ret/Mash1/TH/DBH expression

    PMID:10360575

    Open questions at the time
    • Did not distinguish direct transcriptional targets from indirect effects
    • Did not map DNA-binding sites in target promoters
  3. 1999 Medium

    Showed Phox2b acts in concert with second-messenger signaling, enhancing cAMP/PKC-mediated activation of the DBH and other promoters, linking the transcription factor to signaling-responsive gene control.

    Evidence Transient transfection reporter assays in PC12h cells with forskolin/phorbol ester stimulation

    PMID:10395798

    Open questions at the time
    • Mechanism of signaling-dependent potentiation not defined
    • Single cell line, reporter-based
  4. 2000 High

    Demonstrated that Phox2b directly drives proneural specification by establishing it controls noradrenergic centers, branchial/visceral motor neuron survival, progenitor cell cycle exit, and a defined target gene cascade.

    Evidence Loss-of-function mouse knockout and gain-of-function chick in ovo electroporation with marker and BrdU analyses

    PMID:10704382 PMID:10736201 PMID:11034547 PMID:11060244

    Open questions at the time
    • Direct vs. indirect target distinction incomplete
    • Did not address paralog-specific division of labor in vivo
  5. 2001 High

    Provided the first direct molecular proof of a target by showing PHOX2B binds and transactivates the Phox2a promoter, positioning it upstream in the autonomic developmental cascade.

    Evidence EMSA and cotransfection reporter assays on the Phox2a promoter

    PMID:11549713

    Open questions at the time
    • In vivo occupancy at this site not yet shown
    • Did not define the full target repertoire
  6. 2002 High

    Resolved the transcriptional logic by showing Phox2b activates proneural genes and represses neurogenesis inhibitors and competing fate determinants, explaining how it switches progenitors to visceral motor identity.

    Evidence Bidirectional chick electroporation and mouse loss-of-function with multiple in situ markers

    PMID:12399315

    Open questions at the time
    • Direct vs. indirect regulation of each target not all established by binding data
    • Cofactor requirements for activation vs. repression not defined
  7. 2003 Medium

    Extended Phox2b function to chemoreceptor and visceral sensory lineages and demonstrated combinatorial action with Mash1 on RGS4, linking the factor to chemosensory anatomy and respiratory phenotypes.

    Evidence Knockout mouse plethysmography, immunostaining, and gain-of-function chick electroporation with Mash1

    PMID:14627646 PMID:14627719

    Open questions at the time
    • Mechanism of CO2/hypoxia response alteration not at single-neuron resolution
    • RGS4 regulation transient and cell-type restricted
  8. 2004 High

    Identified the upstream control of Phox2b, showing Hoxb1/Hoxb2 via Pbx/Meis sites and Nkx2.2 derepression set its rhombomere-restricted expression, placing it within the hindbrain patterning hierarchy.

    Evidence Reporter assays with enhancer deletions/mutations, EMSA for ternary complexes, chick hindbrain electroporation

    PMID:15289435

    Open questions at the time
    • Did not address how this enhancer integrates with autoregulation
    • In vivo necessity of individual sites not tested by knock-in
  9. 2005 High

    Established the molecular pathology of PHOX2B mutations, distinguishing polyalanine expansions (length-dependent loss of binding, activity, and cytoplasmic/nucleolar mislocalization) from frameshift mutations acting through distinct mechanisms, and identified autoregulation and TLX2 as direct targets.

    Evidence Transactivation reporter and DNA-binding assays, immunofluorescence, ChIP/EMSA on PHOX2B, TLX2, DBH, PHOX2A promoters in cell lines

    PMID:15733675 PMID:15888479 PMID:16144830 PMID:16249188 PMID:16402914

    Open questions at the time
    • In vivo consequences of distinct mutation classes not yet modeled
    • Quantitative contribution of aggregation vs. mislocalization to disease unresolved at this stage
  10. 2008 High

    Modeled CCHS in vivo and identified ALK as a direct target, showing the 27Ala expansion specifically eliminates glutamatergic parafacial/RTN neurons and abolishes CO2 responsiveness, pinpointing the cellular substrate of breathing automaticity.

    Evidence 27Ala knock-in mouse with plethysmography and brainstem immunostaining; ChIP, siRNA, and overexpression for ALK; yeast two-hybrid and co-expression for Trim11

    PMID:18198276 PMID:18275850 PMID:20957039

    Open questions at the time
    • Mechanism linking RTN loss to apnea at circuit level not yet defined
    • Trim11 functional role limited to a single culture readout
  11. 2009 Medium

    Showed PHOX2B cooperates with Sox10 and Nkx2-1 at the RET promoter and is present in mature enteric ganglia, connecting it to enteric neural crest gene regulation relevant to Hirschsprung disease.

    Evidence Dual-luciferase cotransfection reporter assays and IHC in human gut

    PMID:19853745

    Open questions at the time
    • Direct DNA binding to the RET promoter not rigorously established
    • Cooperativity mechanism with Sox10/Nkx2-1 not structurally defined
  12. 2011 High

    Revealed PHOX2B as a binary fate switch, demonstrating that without it surviving cranial sensory neurons adopt somatic rather than visceral identity, defining a developmental decision point.

    Evidence Genetic lineage tracing in Phox2b conditional knockout mice with marker and projection analysis

    PMID:22128334

    Open questions at the time
    • Direct target genes mediating the somatic-to-visceral switch not identified
    • Cofactors specifying the alternate fate unknown
  13. 2012 High

    Distinguished mutation-class-specific disease mechanisms in vivo, showing nonpolyalanine and frameshift mutations exert dominant-negative effects and a gain-of-function that flips a Sox10 enhancer from repression to activation, biasing progenitors toward glial lineage.

    Evidence Knock-in mouse, reporter assays for DBH and Sox10 enhancer, Sox10 immunostaining; equimolar co-transfection and zebrafish morpholino/overexpression models

    PMID:22922260 PMID:23103552 PMID:23754957

    Open questions at the time
    • Structural basis of the repression-to-activation switch unresolved
    • Relative contribution of dominant-negative vs. gain-of-function to each disease phenotype not quantified
  14. 2015 High

    Defined the chemoreflex circuit, showing Atoh1/Phox2b RTN neurons are necessary and sufficient to entrain respiratory rhythm and mediate the pH/CO2 response through glutamatergic transmission.

    Evidence Intersectional Atoh1 x Phox2b genetics with optogenetics, conditional knockout, glutamate-release disruption, and plethysmography

    PMID:25866925

    Open questions at the time
    • Molecular identity of the pH sensor in these neurons not defined here
    • Phox2b transcriptional targets maintaining RTN function unknown
  15. 2017 High

    Identified intrinsic chemosensitivity in Phox2b NTS neurons and showed PHOX2B polyalanine contractions reduce RET transactivation, broadening the genotype-phenotype spectrum toward Hirschsprung predisposition.

    Evidence Patch-clamp of Phox2b+ NTS neurons with targeted lesion and plethysmography; luciferase RET-promoter assays for contraction variants

    PMID:28433712 PMID:28488367

    Open questions at the time
    • Background K+ channel mediating NTS chemosensitivity not molecularly identified
    • RET-contraction effect lacks in vivo validation
  16. 2019 High

    Resolved how Phox2b NTS neurons drive breathing, showing chemogenetic activation increases ventilation and synergizes with CO2, with direct projections to the preBötzinger complex.

    Evidence hM3Dq chemogenetics, ablation, and tract tracing in Phox2b-Cre mice with plethysmography

    PMID:30626698

    Open questions at the time
    • Transcriptional targets sustaining NTS chemosensory function not defined
    • Integration of NTS and RTN inputs to respiratory rhythm not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct PHOX2B mutation classes produce the spectrum of CCHS, neuroblastoma, and Hirschsprung phenotypes at the level of target-gene rewiring and protein dynamics, and which downstream targets maintain chemosensory neuron function, remains incompletely resolved.
  • No structural model linking polyalanine length to aggregation and import loss
  • Comprehensive in vivo target map of PHOX2B not established
  • Molecular pH/CO2 sensor in Phox2b chemosensory neurons unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 7
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005730 nucleolus 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-112316 Neuronal System 4
Partners
ASCL1HAND2NKX2-1PHOX2ASOX10TRIM11

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Phox2b is required for the formation of all autonomic ganglia (sympathetic, parasympathetic, enteric) and three cranial sensory ganglia; in mutant mice, Phox2b is needed for expression of the GDNF-receptor subunit Ret and for maintaining Mash1 expression in ganglionic anlagen, and for activating dopamine-beta-hydroxylase and tyrosine hydroxylase genes required for noradrenergic neurotransmitter biosynthesis. Targeted gene knockout in mice with analysis of ganglionic development, Ret expression, Mash1 expression, and TH/DBH gene activation Nature High 10360575
1997 Phox2b and Phox2a are co-expressed in autonomic and cranial motor neurons; Phox2b expression precedes Phox2a at most sites; loss of Phox2a results in loss of Phox2b expression in cranial ganglia, indicating positive cross-regulation between the two genes. In situ hybridization and immunostaining in wild-type and Phox2a knockout mouse embryos; temporal expression analysis Development (Cambridge, England) Medium 9374403
1998 Phox2a and Phox2b both bind to homeodomain (HD)-binding sites within the dopamine beta-hydroxylase (DBH) promoter domain IV and activate DBH transcription; forced expression of either protein robustly activates DBH promoter in DBH-negative cell lines (>10-fold); neither protein transactivated tyrosine hydroxylase transcription, demonstrating differential target gene selectivity. Reporter gene transfection assays, EMSA (electrophoretic mobility shift assay) for DNA binding, forced expression in DBH-negative cell lines Journal of neurochemistry High 9798905
2000 Phox2b is required for formation of all branchial and visceral (but not somatic) motor neurons in the hindbrain; in Phox2b-null mice, motor neuron precursors die in the neuroepithelium or fail to activate early postmitotic markers and fail to downregulate neuroepithelial markers. Targeted gene knockout in mice with histological and molecular marker analysis of motor neuron differentiation Development (Cambridge, England) High 10704382
2000 Phox2b is required for differentiation of all central noradrenergic centers (including locus coeruleus), making it a master regulator of all central and peripheral noradrenergic differentiation; Phox2b knockout mice lack TH and DBH expression in all noradrenergic brain centers. Phox2b knockout mouse analysis with immunostaining for TH and DBH in noradrenergic brain centers Molecular and cellular neurosciences High 10736201
2000 Phox2b drives neuronal progenitor cell cycle exit: loss-of-function reduces generation of post-mitotic neuronal precursors; gain-of-function (forced expression in chick spinal cord) drives ventricular zone progenitors to become post-mitotic neurons and relocate to mantle layer, initiating a motor neuronal differentiation program (Islet1 expression, cholinergic transmitter phenotype). Loss-of-function mouse knockout and gain-of-function chick in ovo electroporation with BrdU incorporation, immunostaining for Islet1 and cholinergic markers Development (Cambridge, England) High 11060244
2001 PHOX2B directly binds to a homeodomain-binding site in the 5' regulatory region of the human Phox2a gene and transactivates Phox2a promoter activity, providing molecular evidence that Phox2b acts upstream of Phox2a in the autonomic nervous system developmental cascade. EMSA demonstrating direct PHOX2B binding to Phox2a promoter site; cotransfection reporter assays showing Phox2b-mediated transactivation of Phox2a promoter The Journal of neuroscience High 11549713
2002 Phox2b upregulates proneural gene Ngn2 when expressed alone, and upregulates Mash1 in combination with Nkx2.2; separately, Phox2b represses inhibitors of neurogenesis Hes5 and Id2; Phox2b also represses Pax6 and Olig2 (inhibiting branchiomotor fate) and induces Nkx6.1/Nkx6.2 (expressed in branchiomotor progenitors); Phox2b acts as a transcriptional activator for both generic neuronal differentiation and Islet1 expression. Gain-of-function chick spinal cord electroporation and loss-of-function mouse analysis with in situ hybridization for Ngn2, Mash1, Hes5, Id2, Pax6, Olig2, Nkx6.1, Nkx6.2, Islet1 Development (Cambridge, England) High 12399315
2003 Phox2b controls differentiation of the carotid body (neural crest-derived peripheral chemoreceptor), epibranchial placode-derived visceral sensory ganglia (geniculate, petrosal, nodose), and the nucleus of the solitary tract; Phox2b heterozygous mutants have altered hypoxia/hypercapnia responses and decreased tyrosine hydroxylase expression in petrosal chemosensory neurons. Phox2b homozygous and heterozygous knockout mouse analysis with whole-body plethysmography, immunostaining, and TH expression quantification Development (Cambridge, England) High 14627719
2003 Phox2b cooperates with Mash1 to transiently activate RGS4 expression in specific peripheral and central neuronal precursors; Phox2b is required for RGS4 expression in the locus coeruleus, sympathetic ganglia, and cranial motor/sensory neurons; Phox2b also controls expression of the Gα-subunit gustducin in facial motor neurons. Phox2b knockout mouse in situ hybridization for RGS4; gain-of-function chick spinal cord electroporation with co-expression of Phox2b and Mash1 The Journal of neuroscience Medium 14627646
2004 Hoxb1 and Hoxb2 directly regulate Phox2b transcription through a conserved proximal enhancer containing separate Pbx-Hox and Prep/Meis binding sites required for rhombomere-restricted expression; the dorsoventral factor Nkx2.2 enhances Hox-mediated transactivation of Phox2b via a derepression mechanism; combined activity of Hox and Nkx2 proteins is required for ectopic Phox2b-expressing visceral motoneuron induction. Reporter gene assays with enhancer deletions and binding-site mutations; EMSA for ternary complex formation; chick hindbrain electroporation gain-of-function Development (Cambridge, England) High 15289435
2005 PHOX2B transactivation of the dopamine beta-hydroxylase promoter is abolished or severely reduced by frameshift and missense mutations; polyalanine tract expansion mutations show length-dependent reduction in transactivation; DNA binding is affected for expansions of +9 alanines and above; cytoplasmic aggregation occurs only for longer expansions (+9 and above), while even short expansion mutants form multimers in vitro. Transactivation reporter assays, in vitro DNA-binding assays, immunofluorescence in transfected cells, gel filtration of in vitro translated proteins Human molecular genetics High 16249188
2005 PHOX2B transcription is maintained by an auto-regulatory mechanism: PHOX2B binds four sites within its own proximal 5' regulatory region (confirmed by ChIP and EMSA), accounting for 65% of PHOX2B promoter activity in neuroblastoma cells; all four binding sites are required for full self-transactivation. Chromatin immunoprecipitation (ChIP), EMSA, deletion and point-mutation reporter assays in neuroblastoma cells The Journal of biological chemistry High 16144830
2005 Phox2b is required for very early differentiation events in adrenal chromaffin cells; Phox2b knockout mice show chromaffin cell arrest at a stage earlier than MASH-1 knockouts, with absence of TH, dHand, Phox2a, c-ret, neurofilament, neuron-specific tubulin, and NCAM, and increased apoptosis. Phox2b knockout/lacZ knockin mouse analysis with immunostaining, electron microscopy, and comparison to MASH-1 knockout Developmental biology High 15733675
2005 Distinct pathogenetic mechanisms underlie polyalanine expansion vs. frameshift PHOX2B mutations: polyalanine expansions cause length-dependent cytoplasmic retention/aggregation and reduced transcriptional activity on DBH and PHOX2A target genes; frameshift mutations do not impair nuclear localization but affect transcriptional activity through a different mechanism; one frameshift mutation causes sequestration of mutant PHOX2B in the nucleolar compartment. Transient transfection transcription reporter assays, immunofluorescence for subcellular localization in transfected cells Human molecular genetics High 15888479
2006 PHOX2B directly binds a cell-specific element in the 5' regulatory region of TLX2 and transactivates TLX2 expression in neuroblastoma cells; this interaction was confirmed in vivo by ChIP; overexpression of PHOX2B upregulates endogenous TLX2 mRNA; CCHS-associated mutant PHOX2B proteins show severely impaired TLX2 transactivation. Transient transfection reporter assays, EMSA, chromatin immunoprecipitation (ChIP), quantitative real-time PCR for endogenous TLX2 The Biochemical journal High 16402914
2008 Mice bearing the Phox2b 27-alanine expansion mutation (a frequent CCHS-causing mutation) specifically lack glutamatergic parafacial/RTN neurons expressing Phox2b, do not respond to elevated CO2, and die from central apnea; no other respiratory neuronal populations were anatomically missing, implicating Phox2b-expressing parafacial neurons as essential for CO2 chemosensitivity and breathing automaticity. Knock-in mouse model with the human CCHS 27Ala mutation; plethysmography, immunostaining for glutamatergic and other neuronal markers in brainstem Proceedings of the National Academy of Sciences of the United States of America High 18198276
2008 PHOX2B directly binds the ALK gene promoter and drives ALK transcription; PHOX2B siRNA knockdown downregulates ALK protein; forced PHOX2B overexpression increases ALK protein levels; PHOX2B and PHOX2A siRNAs efficiently downregulate each other as well as ALK. siRNA knockdown, forced overexpression, ChIP demonstrating PHOX2B binding to ALK promoter, Western blot for ALK protein PloS one Medium 20957039
2008 Trim11 physically interacts with Phox2b (interaction requires the B30.2/SPRY domain of Trim11); co-expression of Trim11 with Phox2b increases DBH mRNA levels beyond what Phox2b alone achieves, suggesting Trim11 potentiates Phox2b-mediated noradrenergic specification. Yeast two-hybrid screening, protein-protein interaction assays, forced co-expression in avian neural crest stem cells with DBH mRNA quantification Biochemical and biophysical research communications Medium 18275850
2009 PHOX2B co-operates with Sox10 and Nkx2-1 to mediate RET promoter transcription; PHOX2B is expressed in mature enteric ganglion cells; a Phox2b-responsive region was identified in the RET promoter. Dual-luciferase reporter assays with co-transfections, immunohistochemistry for PHOX2B in human gut Journal of pediatric surgery Medium 19853745
2010 Neuroblastoma-associated PHOX2B mutations with homeodomain alterations cause increased proliferation of sympathetic neurons when endogenous Phox2b is reduced by siRNA, and this effect is blocked by Hand2 knockdown; Hand2 overexpression rescues the antiproliferative effect of wild-type Phox2b, implicating Hand2 in Phox2b-mediated proliferation control. siRNA knockdown of endogenous Phox2b combined with forced expression of mutant Phox2b variants in primary embryonic chick sympathetic neurons; BrdU incorporation; Hand2 knockdown/overexpression The Journal of neuroscience Medium 20089899
2011 Phox2b acts as a developmental switch converting cranial sensory neurons from somatic to visceral fate; genetically traced Phox2b+ cells that survive in the absence of Phox2b adopt molecular signatures, cell positions, and axonal projections characteristic of somatic sensory neurons rather than visceral sensory neurons. Genetic lineage tracing of Phox2b+ cells in Phox2b conditional knockout mice; immunostaining and axonal projection analysis Proceedings of the National Academy of Sciences of the United States of America High 22128334
2012 Nonpolyalanine repeat expansion mutations of PHOX2B act as both dominant-negative and gain-of-function mutations: mutant PHOX2B reduces transactivation of DBH in a dominant-negative fashion; mutant PHOX2B converts the transcriptional effect on a Sox10 enhancer from repression to transactivation, causing sustained Sox10 expression and biased glial lineage differentiation in enteric and sympathetic progenitors. Knock-in mouse model; reporter assays for DBH transactivation and Sox10 enhancer activity; immunostaining for Sox10 in mutant embryos The Journal of clinical investigation High 22922260
2012 Polyalanine expansion mutations of PHOX2B reduce transactivation activity on the PHOX2B auto-regulatory promoter in a length-dependent manner; co-transfection of wild-type and mutant PHOX2B at equimolar amounts demonstrates promoter-specific dominant-negative effects; the longest expansion (+13Ala) severely impairs DNA binding and causes cytoplasmic aggregation sequestering wild-type protein; deletion of the PHOX2B C-terminus impairs wild-type transcriptional activity without mislocalization, indicating mislocalization is not the sole pathogenic mechanism. Transient transfection reporter assays for PHOX2B, PHOX2A, DBH, and TLX2 promoters; immunofluorescence for subcellular localization; co-transfection with equimolar amounts to simulate heterozygosity Neurobiology of disease High 23103552
2013 Phox2b regulates its own expression (autoregulation) and also regulates ascl1; phox2b deficiency uncouples the phox2b-ascl1 autoregulatory mechanism, leading to inhibition of sympathetic neuron terminal differentiation (loss of th and dbh expression); frameshift neuroblastoma mutations 676delG and K155X (but not R100L missense) exert dominant-negative effects on sympathetic differentiation when co-expressed with endogenous Phox2b. Zebrafish phox2b morpholino knockdown; overexpression of wild-type and neuroblastoma mutant phox2b; in situ hybridization for th, dbh, ascl1 in sympathetic ganglia PLoS genetics Medium 23754957
2015 Retrotrapezoid nucleus (RTN) neurons co-expressing Atoh1 and Phox2b are a necessary component of the respiratory chemoreflex circuit: photostimulation of these neurons entrains respiratory rhythm; ablation or knockout of Atoh1 or Phox2b, or disruption of glutamatergic transmission in these cells abolishes the phrenic nerve response to low pH in embryonic preparations and abolishes the respiratory chemoreflex in behaving animals. Intersectional genetic strategy (Atoh1 x Phox2b) with optogenetic activation, conditional ablation, conditional knockout of Phox2b/Atoh1, and conditional disruption of glutamate release; in vivo plethysmography eLife High 25866925
2016 PHOX2B forms homodimers and heterodimers with PHOX2A via its homeodomain; the polyalanine tract is not directly required for dimer formation; polyalanine-expanded mutant proteins retain partial ability to form heterodimers with PHOX2A but do not efficiently form homodimers with wild-type PHOX2B; the longest polyalanine expansions impair homeodomain-mediated nuclear import. Co-immunoprecipitation assay, mammalian two-hybrid system, nuclear import assays The Journal of biological chemistry Medium 27129232
1999 NBPhox/PHOX2B substantially enhances second messenger-mediated (cAMP/PKC) activation of the DBH promoter in PC12h cells; it also potentiates activation of the c-fos promoter and cAMP-response element, AP-1 binding site, and serum-response element reporters; minimal effect without second messenger stimulation. Transient transfection reporter assays in PC12h cells with forskolin/phorbol ester stimulation Genomics Medium 10395798
2000 Phox2b (NBPhox) and Phox2a (Arix) bind to three sites in the DBH proximal promoter; in vitro both proteins form DNA-independent multimers and show cooperative binding to the DB1 regulatory element (which contains two HD recognition sites); transcription from the DBH promoter is synergistically increased by PKA plus either Phox2b or Phox2a; co-expression of both proteins gives transcriptional activation equivalent to either alone (no synergy between the paralogs on this promoter). In vitro DNA binding assays, gel shift (cooperative binding), reporter transcription assays with PKA co-transfection DNA and cell biology Medium 11034547
2017 Phox2b-expressing NTS neurons exhibit intrinsic CO2/H+ chemosensitivity (sustained or transient firing rate increase upon acidification preserved in dissociated neurons); a background K+ channel-like current contributes to this chemosensitivity; ablation of ~18% of Phox2b-expressing NTS neurons significantly reduces hypercapnic ventilatory response. Substance P-saporin lesion of Phox2b+ NTS neurons in Phox2b-EGFP mice; patch-clamp recordings in brainstem slices and dissociated neurons; whole-body plethysmography The Journal of physiology High 28488367
2019 Chemogenetic activation of Phox2b-expressing NTS neurons increases baseline ventilation (minute volume via respiratory frequency) and synergizes with CO2 stimulation; selective ablation of these neurons attenuates the hypercapnic ventilatory response; anatomical tracing shows direct projection of Phox2b-expressing NTS neurons to the preBötzinger complex. Cre-dependent hM3Dq chemogenetic activation in Phox2b-Cre mice; whole-body plethysmography; targeted neuronal ablation; neuroanatomical tract tracing The Journal of neuroscience High 30626698
2017 Common PHOX2B polyalanine contractions reduce transactivation of the RET promoter in a length-dependent manner in vitro, with a milder effect than CCHS-associated polyalanine expansions, providing a mechanism by which PHOX2B variants predispose to Hirschsprung disease through reduced RET expression. Luciferase reporter assays for RET promoter transactivation by multiple PHOX2B polyalanine contraction variants Biochimica et biophysica acta. Molecular basis of disease Medium 28433712

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Nature 696 10360575
2003 Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nature genetics 639 12640453
1997 Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis. Development (Cambridge, England) 490 9374403
2006 Expression of Phox2b by brainstem neurons involved in chemosensory integration in the adult rat. The Journal of neuroscience : the official journal of the Society for Neuroscience 297 17021186
2004 Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. American journal of human genetics 254 15024693
2008 A human mutation in Phox2b causes lack of CO2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons. Proceedings of the National Academy of Sciences of the United States of America 246 18198276
2003 Phox2b controls the development of peripheral chemoreceptors and afferent visceral pathways. Development (Cambridge, England) 245 14627719
2000 Control of hindbrain motor neuron differentiation by the homeobox gene Phox2b. Development (Cambridge, England) 183 10704382
1998 A single rostrocaudal colonization of the rodent intestine by enteric neuron precursors is revealed by the expression of Phox2b, Ret, and p75 and by explants grown under the kidney capsule or in organ culture. Developmental biology 182 9758704
2005 PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. American journal of human genetics 181 15657873
2000 Specification of the central noradrenergic phenotype by the homeobox gene Phox2b. Molecular and cellular neurosciences 175 10736201
2006 Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. American journal of respiratory and critical care medicine 171 16888290
1999 Expression of Ret-, p75(NTR)-, Phox2a-, Phox2b-, and tyrosine hydroxylase-immunoreactivity by undifferentiated neural crest-derived cells and different classes of enteric neurons in the embryonic mouse gut. Developmental dynamics : an official publication of the American Association of Anatomists 158 10536054
2008 CO2-sensitive preinspiratory neurons of the parafacial respiratory group express Phox2b in the neonatal rat. The Journal of neuroscience : the official journal of the Society for Neuroscience 132 19036978
2009 Acid sensitivity and ultrastructure of the retrotrapezoid nucleus in Phox2b-EGFP transgenic mice. The Journal of comparative neurology 124 19711410
2007 Prevalence and functional consequence of PHOX2B mutations in neuroblastoma. Oncogene 118 17637745
2007 Central nervous system distribution of the transcription factor Phox2b in the adult rat. The Journal of comparative neurology 116 17559094
1998 Paired-like homeodomain proteins, Phox2a and Phox2b, are responsible for noradrenergic cell-specific transcription of the dopamine beta-hydroxylase gene. Journal of neurochemistry 115 9798905
2005 Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. Human molecular genetics 114 16249188
2004 The Phox2B homeobox gene is mutated in sporadic neuroblastomas. Oncogene 101 15516980
2011 Homeoprotein Phox2b commands a somatic-to-visceral switch in cranial sensory pathways. Proceedings of the National Academy of Sciences of the United States of America 96 22128334
2000 The Phox2b transcription factor coordinately regulates neuronal cell cycle exit and identity. Development (Cambridge, England) 92 11060244
2005 Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome. Human molecular genetics 88 15888479
2012 Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression. The Journal of clinical investigation 85 22922260
2008 PHOX2B is a novel and specific marker for minimal residual disease testing in neuroblastoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 84 18838715
2015 The retrotrapezoid nucleus neurons expressing Atoh1 and Phox2b are essential for the respiratory response to CO₂. eLife 81 25866925
2008 Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death. Pediatric pulmonology 76 18041756
2009 Phox2b, RTN/pFRG neurons and respiratory rhythmogenesis. Respiratory physiology & neurobiology 71 19712902
2007 PHOX2B germline and somatic mutations in late-onset central hypoventilation syndrome. American journal of respiratory and critical care medicine 70 18079495
2008 The MSX1 homeobox transcription factor is a downstream target of PHOX2B and activates the Delta-Notch pathway in neuroblastoma. Experimental cell research 66 18201699
2005 The role of Phox2B in chromaffin cell development. Developmental biology 63 15733675
2005 Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Cancer letters 61 15949893
2003 Association study of PHOX2B as a candidate gene for Hirschsprung's disease. Gut 61 12631670
2004 Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B. Human molecular genetics 60 14709596
2010 Congenital central hypoventilation syndrome and the PHOX2B gene: a model of respiratory and autonomic dysregulation. Respiratory physiology & neurobiology 58 20601214
2009 PHOX2B in respiratory control: lessons from congenital central hypoventilation syndrome and its mouse models. Respiratory physiology & neurobiology 54 19712905
2019 Causative and common PHOX2B variants define a broad phenotypic spectrum. Clinical genetics 53 31444792
2002 The role of Phox2b in synchronizing pan-neuronal and type-specific aspects of neurogenesis. Development (Cambridge, England) 53 12399315
2010 Neuroblastoma phox2b variants stimulate proliferation and dedifferentiation of immature sympathetic neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 52 20089899
2013 Distinct neuroblastoma-associated alterations of PHOX2B impair sympathetic neuronal differentiation in zebrafish models. PLoS genetics 50 23754957
2004 Integration of anteroposterior and dorsoventral regulation of Phox2b transcription in cranial motoneuron progenitors by homeodomain proteins. Development (Cambridge, England) 50 15289435
2003 Dynamic expression of RGS4 in the developing nervous system and regulation by the neural type-specific transcription factor Phox2b. The Journal of neuroscience : the official journal of the Society for Neuroscience 50 14627646
2009 Transcriptional regulation of RET by Nkx2-1, Phox2b, Sox10, and Pax3. Journal of pediatric surgery 48 19853745
2017 Chemosensitive Phox2b-expressing neurons are crucial for hypercapnic ventilatory response in the nucleus tractus solitarius. The Journal of physiology 45 28488367
2006 PHOX2B analysis in non-syndromic neuroblastoma cases shows novel mutations and genotype-phenotype associations. American journal of medical genetics. Part A 45 16691592
2001 Sp proteins and Phox2b regulate the expression of the human Phox2a gene. The Journal of neuroscience : the official journal of the Society for Neuroscience 45 11549713
2000 Paired-like homeodomain proteins Phox2a/Arix and Phox2b/NBPhox have similar genetic organization and independently regulate dopamine beta-hydroxylase gene transcription. DNA and cell biology 45 11034547
2008 A Histone2BCerulean BAC transgene identifies differential expression of Phox2b in migrating enteric neural crest derivatives and enteric glia. Developmental dynamics : an official publication of the American Association of Anatomists 44 18351668
2013 A study of gata3 and phox2b expression in tumors of the autonomic nervous system. The American journal of surgical pathology 43 23715162
2012 PHOX2B immunolabeling: a novel tool for the diagnosis of undifferentiated neuroblastomas among childhood small round blue-cell tumors. The American journal of surgical pathology 42 22790854
2006 The TLX2 homeobox gene is a transcriptional target of PHOX2B in neural-crest-derived cells. The Biochemical journal 42 16402914
2003 PMX2B, a new candidate gene for Hirschsprung's disease. Clinical genetics 42 12919134
2019 Activation of Phox2b-Expressing Neurons in the Nucleus Tractus Solitarii Drives Breathing in Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 41 30626698
2017 PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours. Histopathology 39 28640941
2005 PHOX2B mutations and genetic predisposition to neuroblastoma. Oncogene 39 15735672
2005 Facial phenotype in children and young adults with PHOX2B-determined congenital central hypoventilation syndrome: quantitative pattern of dysmorphology. Pediatric research 39 16327002
2004 PHOX2B gene mutation in a patient with late-onset central hypoventilation. Pediatric pulmonology 39 15334515
2013 A Phox2b::FLPo transgenic mouse line suitable for intersectional genetics. Genesis (New York, N.Y. : 2000) 38 23592597
2019 Chemosensitivity of Phox2b-expressing retrotrapezoid neurons is mediated in part by input from 5-HT neurons. The Journal of physiology 37 30866045
2010 PHOX2B-mediated regulation of ALK expression: in vitro identification of a functional relationship between two genes involved in neuroblastoma. PloS one 37 20957039
2005 PHOX2B regulates its own expression by a transcriptional auto-regulatory mechanism. The Journal of biological chemistry 36 16144830
2010 PHOX2B immunolocalization of the candidate human retrotrapezoid nucleus. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 35 19888871
2012 Transcriptional dysregulation and impairment of PHOX2B auto-regulatory mechanism induced by polyalanine expansion mutations associated with congenital central hypoventilation syndrome. Neurobiology of disease 33 23103552
2017 Structural and functional differences in PHOX2B frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome. Human mutation 32 29098737
2009 In Vitro studies of non poly alanine PHOX2B mutations argue against a loss-of-function mechanism for congenital central hypoventilation. Human mutation 32 19058226
2004 Interaction of Mash1 and Phox2b in sympathetic neuron development. Molecular and cellular neurosciences 32 15033166
2015 Diagnostic utility of PHOX2B in primary and treated neuroblastoma and in neuroblastoma metastatic to the bone marrow. Archives of pathology & laboratory medicine 31 25822764
2009 PHOX2B mutation-confirmed congenital central hypoventilation syndrome in a Chinese family: presentation from newborn to adulthood. Chest 30 19201717
2006 Geldanamycin promotes nuclear localisation and clearance of PHOX2B misfolded proteins containing polyalanine expansions. The international journal of biochemistry & cell biology 29 17045833
2005 Phox2B mutations and the Delta-Notch pathway in neuroblastoma. Cancer letters 29 16084642
2017 Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome. American journal of medical genetics. Part A 27 28371199
2010 IL23R, NOD2/CARD15, ATG16L1 and PHOX2B polymorphisms in a group of patients with Crohn's disease and correlation with sub-phenotypes. International journal of molecular medicine 27 21206965
2011 In vitro drug treatments reduce the deleterious effects of aggregates containing polyAla expanded PHOX2B proteins. Neurobiology of disease 26 21964250
2004 Haploinsufficiency for Phox2b in mice causes dilated pupils and atrophy of the ciliary ganglion: mechanistic insights into human congenital central hypoventilation syndrome. Human molecular genetics 26 15150159
2017 Common PHOX2B poly-alanine contractions impair RET gene transcription, predisposing to Hirschsprung disease. Biochimica et biophysica acta. Molecular basis of disease 25 28433712
2005 Pediatric disorders with autonomic dysfunction: what role for PHOX2B? Pediatric research 25 15901893
2004 Sudden infant death syndrome is not associated with the mutation of PHOX2B gene, a major causative gene of congenital central hypoventilation syndrome. The Tohoku journal of experimental medicine 25 15185974
2021 Paired-like homeobox gene (PHOX2B) nonpolyalanine repeat expansion mutations (NPARMs): genotype-phenotype correlation in congenital central hypoventilation syndrome (CCHS). Genetics in medicine : official journal of the American College of Medical Genetics 24 33958749
2017 The transcription factor Phox2b distinguishes between oral and non-oral sensory neurons in the geniculate ganglion. The Journal of comparative neurology 24 28856690
2007 Vagal and sympathetic heart rate and blood pressure control in adult onset PHOX2B mutation-confirmed congenital central hypoventilation syndrome. Clinical autonomic research : official journal of the Clinical Autonomic Research Society 24 17541758
2017 Utility of Phox2b immunohistochemical stain in neural crest tumours and non-neural crest tumours in paediatric patients. Histopathology 23 28986989
2008 Homozygous mutation of the PHOX2B gene in congenital central hypoventilation syndrome (Ondine's Curse). Human mutation 22 18407552
2005 Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders: evidence for association of ASCL1 with Parkinson's disease. Human genetics 22 16021468
2018 Adult With PHOX2B Mutation and Late-Onset Congenital Central Hypoventilation Syndrome. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 21 30518452
2008 PHOX2A and PHOX2B genes are highly co-expressed in human neuroblastoma. International journal of oncology 21 18949361
2007 Unequal crossover recombination - population screening for PHOX2B gene polyalanine polymorphism using CE. Electrophoresis 21 17300129
1999 Genomic structure and functional characterization of NBPhox (PMX2B), a homeodomain protein specific to catecholaminergic cells that is involved in second messenger-mediated transcriptional activation. Genomics 21 10395798
2014 Cytoarchitecture and CO(2) sensitivity of Phox2b-positive Parafacial neurons in the newborn rat medulla. Progress in brain research 20 24746043
2012 Relationship between the distribution of the paired-like homeobox gene (Phox2b) expressing cells and blood vessels in the parafacial region of the ventral medulla of neonatal rats. Neuroscience 20 22521817
2009 rs224136 on chromosome 10q21.1 and variants in PHOX2B, NCF4, and FAM92B are not major genetic risk factors for susceptibility to Crohn's disease in the German population. The American journal of gastroenterology 20 19262523
2007 Transcriptional regulation of TLX2 and impaired intestinal innervation: possible role of the PHOX2A and PHOX2B genes. European journal of human genetics : EJHG 20 17505528
2017 Three-Generation Family With Congenital Central Hypoventilation Syndrome and Novel PHOX2B Gene Non-Polyalanine Repeat Mutation. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 19 28633714
2015 A Phox2b BAC Transgenic Rat Line Useful for Understanding Respiratory Rhythm Generator Neural Circuitry. PloS one 19 26147470
2012 Associations between variants near a monoaminergic pathways gene (PHOX2B) and amygdala reactivity: a genome-wide functional imaging study. Twin research and human genetics : the official journal of the International Society for Twin Studies 19 22856363
2008 PHOX2B mutations and ventilatory control. Respiratory physiology & neurobiology 19 18675942
2007 Methylation-associated PHOX2B gene silencing is a rare event in human neuroblastoma. European journal of cancer (Oxford, England : 1990) 19 17765533
2001 Structural and functional characterization of the 5' upstream promoter of the human Phox2a gene: possible direct transactivation by transcription factor Phox2b. Journal of neurochemistry 19 11752063
2016 Alanine Expansions Associated with Congenital Central Hypoventilation Syndrome Impair PHOX2B Homeodomain-mediated Dimerization and Nuclear Import. The Journal of biological chemistry 18 27129232
2014 Late-onset congenital central hypoventilation syndrome and a rare PHOX2B gene mutation. Sleep & breathing = Schlaf & Atmung 18 24792884
2008 Trim11 increases expression of dopamine beta-hydroxylase gene by interacting with Phox2b. Biochemical and biophysical research communications 18 18275850

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