Affinage

PHOX2A

Paired mesoderm homeobox protein 2A · UniProt O14813

Length
284 aa
Mass
29.7 kDa
Annotated
2026-06-10
55 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PHOX2A is a paired-like homeodomain transcription factor that specifies noradrenergic and autonomic neuronal identity during development (PMID:9115735, PMID:10595509). It is positioned within a defined regulatory cascade: MASH1 acts upstream to drive Phox2a expression in noradrenergic centers and autonomic ganglia (PMID:9435281, PMID:9435282), and FGF8 and BMP signals from the mid/hindbrain boundary control its induction in locus coeruleus progenitors (PMID:10595509), while PHOX2B directly binds and transactivates the PHOX2A promoter (PMID:11549713); Phox2a in turn cross-regulates Phox2b at cranial ganglia, making the two factors mutually dependent in distinct contexts (PMID:9374403). Its principal transcriptional target is the dopamine-β-hydroxylase (DBH) gene, which it activates in a noradrenergic-specific manner by binding multiple homeodomain sites in the proximal promoter—engaging PBD1 as a monomer and PBD2/PBD3 as dimers—with target selectivity such that it activates DBH but not tyrosine hydroxylase (PMID:9798905, PMID:9763470, PMID:11948255). Activation is synergistic with the cAMP/PKA pathway and is potentiated by the co-activator CBP, which binds the N-terminal activation domain, and by HAND2, which directly interacts with PHOX2A to enhance DBH transcription (PMID:9341190, PMID:10644760, PMID:14512028, PMID:14506227). PHOX2A activity is gated by phosphorylation: constitutive phosphorylation is removed by PP2A-like dephosphorylation at Ser206 to enable DNA binding, followed after a delay by PKA-dependent rephosphorylation at Ser153 that terminates activity, while ERK1/2 phosphorylation in the N-terminal domain negatively regulates target engagement (PMID:11943777, PMID:16204240, PMID:19564421, PMID:16156742). Beyond noradrenergic enzyme genes, PHOX2A induces the cell-cycle inhibitor p27Kip1 to couple cell-cycle exit to differentiation, transactivates TLX2, and regulates the α3 nicotinic receptor subunit gene through a DNA-independent interaction with Sp1 (PMID:16982676, PMID:17344216, PMID:17505528). In the mature nervous system PHOX2A is required for oculomotor and trochlear nucleus development—homozygous PHOX2A mutations cause congenital fibrosis of the extraocular muscles type 2 (CFEOM2) (PMID:11600883, PMID:20215354)—for locus coeruleus-dependent respiratory rhythm maturation (PMID:14749437), and for formation of the anterolateral system nociceptive relay from spinal cord to brain (PMID:33238113, PMID:36028316).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1997 High

    Established PHOX2A as an essential developmental regulator by showing its loss eliminates specific noradrenergic and autonomic neuronal populations and triggers apoptosis.

    Evidence Targeted Phox2a knockout mice with immunohistochemistry and in situ hybridization

    PMID:9115735 PMID:9374403

    Open questions at the time
    • Did not establish direct transcriptional targets
    • Cross-regulation with Phox2b directionally context-dependent and not resolved mechanistically
  2. 1997 High

    Identified DBH as a direct functional target and revealed that PHOX2A requires cAMP synergy rather than acting alone.

    Evidence Reporter assays with PKA cotransfection and EMSA supershift in non-neuronal cells

    PMID:9341190

    Open questions at the time
    • Did not map the phosphorylation events linking cAMP to PHOX2A activity
    • Mechanism of synergy not defined at the protein level
  3. 1998 High

    Defined the cell-specific DNA-binding architecture of PHOX2A on the DBH promoter and demonstrated target selectivity versus tyrosine hydroxylase.

    Evidence EMSA, Southwestern, supershift, and mutant reporter constructs in noradrenergic and DBH-negative cell lines

    PMID:9763470 PMID:9798905

    Open questions at the time
    • Monomer vs dimer occupancy not yet resolved
    • Co-factors mediating selectivity unknown
  4. 1998 High

    Placed PHOX2A downstream of MASH1 and showed it specifies a subtype-specific, not pan-neuronal, identity program.

    Evidence Mash1 knockout in situ analysis and retroviral MASH1/Phox2a forced expression in neural crest stem cells

    PMID:9435281 PMID:9435282

    Open questions at the time
    • Additional targets beyond c-RET not identified
    • Does not explain how pan-neuronal differentiation is supplied
  5. 1999 High

    Demonstrated PHOX2A is both necessary and sufficient for noradrenergic neuron formation in vivo and identified FGF8/BMP as upstream inducers.

    Evidence Zebrafish soulless mutant, ectopic overexpression, and morpholino knockdown

    PMID:10595509

    Open questions at the time
    • Signaling link from FGF8/BMP to Phox2a transcription not mapped
    • Target gene readout limited to DBH/TH/Phox2b
  6. 2000 High

    Mapped PHOX2A functional domains and identified CBP as a co-activator potentiating PKA-dependent transcription, plus DNA-independent multimerization.

    Evidence One- and two-hybrid assays, deletion analysis, and homeodomain-site mutagenesis

    PMID:10644760 PMID:11034547

    Open questions at the time
    • Stoichiometry and functional role of multimers in vivo unclear
    • How N-terminal domain engages the transcription machinery not defined
  7. 2001 High

    Established the regulatory loop with PHOX2B by showing PHOX2B directly binds and transactivates the PHOX2A promoter.

    Evidence EMSA, promoter deletion, and cotransfection reporter assays

    PMID:11549713 PMID:11752063

    Open questions at the time
    • In vivo significance of direct binding versus genetic cross-regulation not separated
    • Tissue specificity of the interaction not resolved
  8. 2001 High

    Linked PHOX2A directly to human disease, demonstrating it is required for oculomotor and trochlear nucleus development.

    Evidence Mutation identification in four CFEOM2 pedigrees

    PMID:11600883

    Open questions at the time
    • Functional consequences of individual mutations not biochemically tested at the time
    • Target genes in oculomotor lineage not defined
  9. 2002 High

    Resolved the binding mode on DBH (monomer at PBD1, dimers at PBD2/3) and tied homeodomain function to in vivo neuron development.

    Evidence EMSA with homeodomain mutants, reporter assays, and antisense injection in zebrafish

    PMID:11948255

    Open questions at the time
    • Determinants of monomer vs dimer site selection not identified
    • Broader target set not surveyed
  10. 2002 High

    Showed that dephosphorylation is the switch coupling PKA signaling to PHOX2A DNA binding and transcription.

    Evidence In vivo phosphorylation assay, EMSA, reporter assays, and phosphatase inhibitor manipulation

    PMID:11943777

    Open questions at the time
    • Specific residues not yet identified
    • Phosphatase identity inferred but not purified
  11. 2003 High

    Identified HAND2 as a direct protein partner that enhances PHOX2A-driven DBH transcription via CBP.

    Evidence Reporter assays, co-immunoprecipitation, E1A inhibition, and HD-site mutagenesis

    PMID:14506227 PMID:14512028

    Open questions at the time
    • Structural basis of the HAND2-PHOX2A interaction unknown
    • In vivo requirement of the interaction not tested
  12. 2005 High

    Demonstrated PKA/PP2A-driven dephosphorylation controls PHOX2A activity and sympathoadrenal lineage development, and that ERK1/2 phosphorylation negatively regulates it.

    Evidence Primary neural crest cultures, pharmacological inhibitors, in vitro binding, reporter assays, and chromatin association/qRT-PCR in SH-SY5Y

    PMID:16156742 PMID:16204240

    Open questions at the time
    • ERK1/2 site mapping correlational in cells
    • Integration of opposing kinase/phosphatase inputs not modeled
  13. 2006 High

    Connected PHOX2A to cell-cycle exit by showing it directly induces p27Kip1 to coordinate proliferation arrest with differentiation.

    Evidence siRNA knockdown, tet-off expression, ChIP, and luciferase reporter assays in CAD and primary neural crest cells

    PMID:16982676

    Open questions at the time
    • Quantitative contribution of p27Kip1 to the differentiation phenotype unclear
    • cAMP dependence mechanism not fully resolved
  14. 2007 High

    Broadened the target repertoire by establishing direct transactivation of TLX2 and a DNA-independent, Sp1-mediated mechanism at the α3 nicotinic receptor promoter.

    Evidence EMSA, ChIP, DNA pulldown, co-immunoprecipitation, and reporter assays

    PMID:17344216 PMID:17505528

    Open questions at the time
    • Generality of the DNA-independent Sp1 mechanism to other targets unknown
    • In vivo relevance of TLX2 regulation not tested
  15. 2009 High

    Defined a two-step phosphorylation timer that initiates and then terminates PHOX2A activity at single-residue resolution.

    Evidence Mass spectrometry, phospho-specific antibody, Ser-to-Ala/Asp mutagenesis, inducible CAD cells, and in vitro binding assays

    PMID:19564421

    Open questions at the time
    • Kinase responsible for delayed Ser153 phosphorylation not purified
    • How timing delay is set mechanistically unknown
  16. 2010 High

    Showed PHOX2A is sufficient to drive the complete oculomotor complex program and organize the nuclear/axonal architecture.

    Evidence In ovo electroporation forced expression in chick midbrain, immunohistochemistry, axon tracing

    PMID:20215354

    Open questions at the time
    • Downstream effectors of spatial organization not identified
    • Direct target genes in motoneuron program not enumerated
  17. 2011 Medium

    Identified Lmx1b as an upstream regulator of Phox2a in the ventral midbrain ocular motor lineage.

    Evidence Lmx1b conditional knockout, immunohistochemistry, in situ hybridization

    PMID:21752929

    Open questions at the time
    • Direct vs indirect regulation by Lmx1b not distinguished
    • Single lab
  18. 2020 High

    Revealed a new circuit role: PHOX2A is required for development of the anterolateral system relaying nociceptive signals from spinal cord to brain.

    Evidence Phox2a::Cre fate mapping, retrograde tracing, knockout analysis in mouse and human fetal spinal cord

    PMID:33238113

    Open questions at the time
    • Direct transcriptional targets in this lineage unknown
    • Molecular link to axon targeting not defined here
  19. 2022 Medium

    Placed DCC/netrin-1 signaling downstream of PHOX2A identity in building somatotopic nociceptive maps.

    Evidence Conditional Dcc knockout in Phox2a neurons, anatomical tracing, topognosis behavior

    PMID:36028316

    Open questions at the time
    • Whether PHOX2A directly regulates DCC not tested
    • Single lab
  20. 2025 Medium

    Extended PHOX2A function to modulation of itch by showing it presynaptically suppresses histamine-independent itch in lateral spinal nucleus Tac1+ neurons.

    Evidence Chemogenetics, whole-cell patch-clamp, Western blot, FISH, and behavioral assays

    PMID:41204431

    Open questions at the time
    • Transcriptional targets mediating the presynaptic effect unknown
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How upstream signaling (FGF8/BMP, MASH1, Lmx1b) is mechanistically wired to PHOX2A's phosphorylation timer and how its target repertoire diversifies across noradrenergic, oculomotor, and somatosensory lineages remains unresolved.
  • No genome-wide target map across the distinct PHOX2A-dependent lineages
  • Kinases/phosphatases acting on PHOX2A in vivo not fully identified
  • Structural basis of monomer/dimer and Sp1/HAND2 interactions undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-112316 Neuronal System 3
Partners
CBPHAND2PHOX2BSP1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Phox2a is required for development of the locus coeruleus, subset of sympathetic/parasympathetic ganglia, and VIIth/IXth/Xth cranial sensory ganglia; in sensory ganglia, Phox2a knockout abolishes transient dopamine-beta-hydroxylase expression in neuroblasts and dramatically reduces Ret expression, leading to massive apoptosis. Targeted gene knockout (Phox2a-/- mice), immunohistochemistry, in situ hybridization Neuron High 9115735
1997 Phox2a positively cross-regulates Phox2b: loss of Phox2b expression is observed in cranial ganglia of Phox2a-deficient mice, indicating Phox2a is upstream of Phox2b at those sites. In situ hybridization in Phox2a knockout mice Development High 9374403
1997 Phox2a (Arix) interacts synergistically with cAMP to activate transcription from the DBH promoter via the DB1 regulatory element; neither Arix nor cAMP alone is sufficient, but together they substantially activate DBH transcription in non-neuronal cells. Transient transfection reporter assay, cotransfection with PKA catalytic subunit, EMSA with antisera supershift The Journal of biological chemistry High 9341190
1998 Phox2a binds the homeodomain-binding site in the DBH promoter domain IV in a noradrenergic cell-specific manner and robustly activates DBH promoter activity (>10-fold) in DBH-negative cell lines; Phox2a does not activate tyrosine hydroxylase transcription, demonstrating selectivity. Electrophoretic mobility shift assay (EMSA), transient transfection reporter assay, forced expression Journal of neurochemistry High 9798905
1998 Phox2a contains at least two binding sites in the DBH upstream promoter (domain IV and domain II); domain II is a second Phox2a-binding site and is a noradrenergic-specific element; four tandem copies of domain II increase minimal DBH promoter activity 100-200 fold in DBH-positive cells. EMSA, competition and antibody supershift assays, Southwestern analysis, transient transfection of mutant reporter constructs The Journal of neuroscience High 9763470
1998 MASH1 is required upstream of Phox2a: Phox2a expression is abolished or massively reduced in Mash1-/- mutant embryos in noradrenergic brain centers and peripheral autonomic ganglia, and constitutive MASH1 expression in neural crest stem cells induces Phox2a expression. In situ hybridization/immunohistochemistry in Mash1 knockout mice; retroviral vector-mediated constitutive MASH1 expression in NCSCs Development High 9435281 9435282
1998 Constitutive Phox2a expression induces c-RET expression but fails to induce pan-neuronal markers or neuronal morphology, indicating Phox2a specifies a subtype-specific (rather than pan-neuronal) component of autonomic neuronal identity. Retroviral constitutive expression in neural crest stem cells, immunostaining Development Medium 9435282
1999 In zebrafish, soulless/Phox2a is not only necessary but sufficient to induce ectopic Phox2b+, dopamine-beta-hydroxylase+, and tyrosine hydroxylase+ noradrenergic neurons; Phox2a expression in locus coeruleus progenitors depends on FGF8 from the mid/hindbrain boundary and BMP signaling. Zebrafish forward genetics (soulless mutation), ectopic Phox2a overexpression, antisense morpholino knockdown Neuron High 10595509
2000 Arix/Phox2a contains an N-terminal activation domain and a C-terminal repression domain; the N-terminal domain contains an amino acid motif similar to Brachyury and Pax9; the N-terminal domain interacts with CBP, and this interaction potentiates PKA-dependent DBH transcription; Arix forms DNA-independent multimers. Mammalian one-hybrid and two-hybrid assays, deletion analysis, site-directed mutagenesis of homeodomain binding sites The Journal of biological chemistry High 10644760
2000 Arix/Phox2a and Phox2b (NBPhox) bind to three sites in the DBH proximal promoter, form DNA-independent multimers, exhibit cooperative binding to the DB1 element (containing two homeodomain recognition sites), and independently stimulate DBH transcription synergistically with PKA; the N-terminal segment is essential for transcriptional activity. In vitro DNA binding assays, transient transfection reporter assay, co-expression experiments DNA and cell biology Medium 11034547
2001 Phox2b binds directly to a homeodomain factor-binding site in the 5' regulatory region of the human Phox2a promoter and transactivates Phox2a expression, providing molecular evidence that Phox2b directly regulates Phox2a transcription. EMSA, cotransfection reporter assay, promoter deletion analysis The Journal of neuroscience High 11549713
2001 Homozygous mutations in PHOX2A/ARIX (two predicted splicing mutations and one missense in the brachyury-like domain) cause congenital fibrosis of the extraocular muscles type 2 (CFEOM2), confirming PHOX2A is required for nIII/nIV oculomotor and trochlear nucleus development in humans. Human genetics — mutation identification by sequencing in four CFEOM2 pedigrees Nature genetics High 11600883
2002 Phox2a directly transactivates the DBH promoter through interactions with four binding sites (PBD1–3) in the proximal promoter; PBD1 interacts with Phox2a monomers while PBD2 and PBD3 interact with Phox2a dimers; homeodomain point mutations abolish both DBH transactivation in vitro and noradrenergic neuron development in vivo (zebrafish). EMSA with homeodomain mutants, transient transfection reporter assay, antisense oligonucleotide injection in zebrafish Journal of neurochemistry High 11948255
2002 Arix/Phox2a is constitutively phosphorylated in vivo; PKA pathway activation decreases Phox2a phosphorylation (dephosphorylation) and coincides with increased Arix DNA-binding activity; phosphatase inhibitors reverse both dephosphorylation and transcriptional activation, demonstrating that dephosphorylation of Phox2a is required for PKA-mediated DBH transcription. In vivo phosphorylation assay, EMSA, reporter assay, pharmacological manipulation (forskolin, phosphatase inhibitors) The Journal of biological chemistry High 11943777
2003 HAND2/dHAND synergistically enhances Phox2a-driven DBH transcription without directly binding to E-box sequences; HAND2 interacts with CBP in the transcriptional complex; the synergistic activation requires Phox2a homeodomain binding sites and is blocked by E1A; dHAND and Arix directly interact by protein-protein interaction (coprecipitation). Transient transfection reporter assay, co-immunoprecipitation, E1A inhibition, mutagenesis of HD-binding sites Developmental biology / The Journal of biological chemistry High 14506227 14512028
2001 Phox2b is capable of transactivating the human Phox2a promoter (but not Phox2a itself or MASH1), as shown by cotransfection assays in Phox2a-negative HeLa cells. Cotransfection reporter assay in HeLa cells Journal of neurochemistry Medium 11752063
1999 Forced expression of Phox2a does not activate the norepinephrine transporter (NET) promoter in NET-negative cell lines, in contrast to its strong activation of the DBH promoter, indicating that distinct molecular mechanisms control NET and DBH cell-specific expression. Transient transfection reporter assay (negative result, mechanistically informative) The Journal of biological chemistry Medium 10037744
2004 Phox2a gene and the A6 (locus coeruleus) noradrenergic neurons it generates are required for normal prenatal maturation of respiratory rhythm; noradrenaline released from A6 neurons potentiates rhythmic respiratory activity via alpha1 medullary adrenoceptors; transynaptic tracing confirmed A6 neurons are connected to the neonatal respiratory network. Phox2a knockout mouse respiratory measurements (in vivo ventilation, in vitro respiratory activity), pharmacological blockade (prazosin), rabies virus transynaptic tracing The Journal of neuroscience High 14749437
2005 cAMP-dependent PKA pathway activates Phox2a by promoting its dephosphorylation (at serine residues), which is required for Phox2a DNA binding and DBH-luciferase reporter expression; inhibition of PKA (H89) or PP2A-like phosphatase (okadaic acid) suppresses Phox2a dephosphorylation, DNA binding, and sympathoadrenal lineage development. Primary neural crest cultures, pharmacological inhibitors, in vitro DNA binding assay, reporter assay, dominant-negative CREB The Journal of biological chemistry High 16204240
2006 Phox2a induces p27Kip1 transcription by binding homeodomain cis-acting elements in the p27Kip1 promoter in vivo (chromatin immunoprecipitation) and mediates p27Kip1-luciferase expression; siRNA silencing of Phox2a suppresses p27Kip1 transcription and neuronal differentiation; this activity requires cAMP signaling. siRNA knockdown, tet-off ectopic expression, chromatin immunoprecipitation, luciferase reporter assay in CAD cells and primary NC cells Molecular and cellular biology High 16982676
2007 PHOX2A regulates the human alpha3 nicotinic acetylcholine receptor subunit gene promoter; PHOX2A assembles on the SacI-NcoI region of the alpha3 promoter (chromatin IP and DNA pulldown); it does not appear to bind DNA directly but interacts with Sp1 by co-immunoprecipitation, regulating alpha3 transcription through a DNA-independent protein-protein interaction mechanism. Chromatin immunoprecipitation, DNA pulldown, co-immunoprecipitation, cotransfection reporter assay The Journal of biological chemistry High 17344216
2009 Phox2a is phosphorylated at a cluster of Ser-Pro sites identified by mass spectrometry; cAMP-dependent activation of Phox2a involves two sequential events: first, dephosphorylation of Ser206 enables DNA binding and p27Kip1 transcription initiation; second, PKA-dependent phosphorylation of Ser153 (after a delay) prevents DNA binding and terminates p27Kip1 transcription. Mass spectrometry phosphorylation site identification, phospho-specific antibody, Ser-to-Ala/Asp mutagenesis, inducible CAD cell lines, in vitro DNA binding assay Molecular and cellular biology High 19564421
2005 ERK1/2 phosphorylates Arix/Phox2a at two sites within the N-terminal transactivation domain; MEK1 inhibition reduces Phox2a phosphorylation in SH-SY5Y cells and increases interaction of Arix with DBH and NET (but not TH) gene targets and elevates DBH and NET mRNAs in sympathetic neurons, indicating ERK1/2-mediated phosphorylation negatively regulates Phox2a transcriptional activity. In vitro kinase assay (implied), MEK1 inhibitors (UO126, PD98059), chromatin association assay, qRT-PCR Journal of neurochemistry Medium 16156742
2007 PHOX2A directly regulates TLX2 transactivation: PHOX2A binds the TLX2 promoter (EMSA and chromatin immunoprecipitation) and transactivates it in cotransfection assays, establishing PHOX2A as part of the cascade leading to TLX2 expression in intestinal neuronal differentiation. Co-transfection reporter assay, EMSA, chromatin immunoprecipitation European journal of human genetics Medium 17505528
2010 Forced expression of PHOX2A in embryonic chick midbrain drives the complete oculomotor complex (OMC) molecular program, producing both visceral and somatic motoneurons and generating ectopic motor nerves that directly innervate extraocular muscle; PHOX2A both specifies motoneuron cell fate and orchestrates spatial organization of the nuclear complex. In ovo electroporation-mediated forced expression in chick midbrain, immunohistochemistry, axon tracing Development High 20215354
2011 Lmx1b regulates Phox2a expression in the ventral midbrain; loss of Lmx1b leads to disrupted Phox2a expression and impaired sequential specification of ocular motor neurons and red nucleus neurons from lateral progenitors. Lmx1b conditional knockout mouse, immunohistochemistry, in situ hybridization Development Medium 21752929
2004 Ciliary neurotrophic factor (CNTF) suppresses Phox2a expression in neuroblastoma cells and cultured sympathetic neurons, and Phox2a is absent in rat cholinergic sympathetic neurons (where noradrenergic enzymes are reduced), suggesting that CNTF-mediated suppression of TH and DBH occurs at least in part through reduction of Phox2a. Immunohistochemistry of sympathetic ganglia, western blot/RT-PCR in neuroblastoma cells and sympathetic neuron cultures Neuroreport Low 15106827
2020 Most mouse spinal neurons that embryonically express Phox2a innervate nociceptive brain targets (parabrachial nucleus and thalamus); Phox2a is required for the development of relay of nociceptive signals from spinal cord to brain, as loss of Phox2a leads to defects in anterolateral system neuron differentiation and nociceptive signaling. Phox2a::Cre fate mapping, retrograde tracing, Phox2a knockout analysis, immunohistochemistry in mouse and human fetal spinal cord Cell reports High 33238113
2022 DCC deletion in Phox2a neurons causes impaired topognosis along the rostrocaudal axis and defective somatotopic targeting of cervical and lumbar anterolateral system axons within the thalamus, placing DCC/netrin-1 signaling downstream of Phox2a neuronal identity in the formation of somatotopically ordered nociceptive maps. Conditional Dcc knockout in Phox2a neurons, anatomical tracing, behavioral assays (topognosis) The Journal of neuroscience Medium 36028316
2023 Prdm12 is required to repress Phox2a/b expression in somatosensory neural precursors; loss of Prdm12 results in ectopic Phox2a and Phox2b expression in trigeminal and dorsal root ganglia, indicating Prdm12 acts upstream of Phox2a to prevent precursors from adopting a visceral neuronal fate. Prdm12 knockout mouse analysis, immunohistochemistry, in situ hybridization iScience Medium 38025786
2025 Phox2a expressed in Tac1+ neurons of the lateral spinal nucleus (LSN) negatively regulates histamine-independent itch; Phox2a is downregulated during chloroquine-induced itch; overexpression of Phox2a in LSNTac1 neurons reduces scratching and decreases spontaneous excitatory postsynaptic current amplitude (without changing frequency), indicating a presynaptic mechanism. Chemogenetic manipulation (viral-mediated activation/inhibition), whole-cell patch-clamp recording, Western blotting, FISH, behavioral assays CNS neuroscience & therapeutics Medium 41204431
2024 A PHOX2A variant (p.Trp137Cys) in the homeodomain reduces or abolishes DNA binding as demonstrated by protein binding microarray, supporting that this residue is critical for PHOX2A transcription factor activity and that this variant is pathogenic in ocular congenital cranial dysinnervation disorder. Protein binding microarray, G0 CRISPR/Cas9 zebrafish knockout screen bioRxivpreprint Medium

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis. Development (Cambridge, England) 490 9374403
1997 Defects in sensory and autonomic ganglia and absence of locus coeruleus in mice deficient for the homeobox gene Phox2a. Neuron 279 9115735
1998 Control of noradrenergic differentiation and Phox2a expression by MASH1 in the central and peripheral nervous system. Development (Cambridge, England) 271 9435281
1998 MASH1 activates expression of the paired homeodomain transcription factor Phox2a, and couples pan-neuronal and subtype-specific components of autonomic neuronal identity. Development (Cambridge, England) 215 9435282
1999 Development of noradrenergic neurons in the zebrafish hindbrain requires BMP, FGF8, and the homeodomain protein soulless/Phox2a. Neuron 192 10595509
2001 Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nature genetics 167 11600883
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
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
2011 Specific and integrated roles of Lmx1a, Lmx1b and Phox2a in ventral midbrain development. Development (Cambridge, England) 106 21752929
1998 Noradrenergic-specific transcription of the dopamine beta-hydroxylase gene requires synergy of multiple cis-acting elements including at least two Phox2a-binding sites. The Journal of neuroscience : the official journal of the Society for Neuroscience 100 9763470
2016 MiR-326 regulates cell proliferation and migration in lung cancer by targeting phox2a and is regulated by HOTAIR. American journal of cancer research 86 27186394
2004 Phox2a gene, A6 neurons, and noradrenaline are essential for development of normal respiratory rhythm in mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 85 14749437
1999 A previously undescribed intron and extensive 5' upstream sequence, but not Phox2a-mediated transactivation, are necessary for high level cell type-specific expression of the human norepinephrine transporter gene. The Journal of biological chemistry 76 10037744
1997 The homeodomain protein Arix interacts synergistically with cyclic AMP to regulate expression of neurotransmitter biosynthetic genes. The Journal of biological chemistry 73 9341190
2020 Phox2a Defines a Developmental Origin of the Anterolateral System in Mice and Humans. Cell reports 51 33238113
2003 HAND2 synergistically enhances transcription of dopamine-beta-hydroxylase in the presence of Phox2a. Developmental biology 49 14512028
2000 The homeodomain protein Arix promotes protein kinase A-dependent activation of the dopamine beta-hydroxylase promoter through multiple elements and interaction with the coactivator cAMP-response element-binding protein-binding protein. The Journal of biological chemistry 46 10644760
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
2002 CFEOM1, the classic familial form of congenital fibrosis of the extraocular muscles, is genetically heterogeneous but does not result from mutations in ARIX. BMC genetics 41 11882252
2003 The interaction between dHAND and Arix at the dopamine beta-hydroxylase promoter region is independent of direct dHAND binding to DNA. The Journal of biological chemistry 38 14506227
2002 A direct role of the homeodomain proteins Phox2a/2b in noradrenaline neurotransmitter identity determination. Journal of neurochemistry 37 11948255
2002 The paired-like homeodomain protein, Arix, mediates protein kinase A-stimulated dopamine beta-hydroxylase gene transcription through its phosphorylation status. The Journal of biological chemistry 31 11943777
2010 PHOX2A regulation of oculomotor complex nucleogenesis. Development (Cambridge, England) 29 20215354
2006 Homeodomain transcription factor Phox2a, via cyclic AMP-mediated activation, induces p27Kip1 transcription, coordinating neural progenitor cell cycle exit and differentiation. Molecular and cellular biology 27 16982676
2007 Transcription factor PHOX2A regulates the human alpha3 nicotinic receptor subunit gene promoter. The Journal of biological chemistry 26 17344216
2003 A novel PHOX2A/ARIX mutation in an Iranian family with congenital fibrosis of extraocular muscles type 2 (CFEOM2). American journal of ophthalmology 26 14597037
2010 Distribution and phenotype of Phox2a-containing neurons in the adult sprague-dawley rat. The Journal of comparative neurology 21 20437524
2009 The Phox2 pathway is differentially expressed in neuroblastoma tumors, but no mutations were found in the candidate tumor suppressor gene PHOX2A. International journal of oncology 21 19212675
2008 PHOX2A and PHOX2B genes are highly co-expressed in human neuroblastoma. International journal of oncology 21 18949361
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
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
2021 Characterisation of lamina I anterolateral system neurons that express Cre in a Phox2a-Cre mouse line. Scientific reports 18 34504158
2005 The cAMP pathway regulates both transcription and activity of the paired homeobox transcription factor Phox2a required for development of neural crest-derived and central nervous system-derived catecholaminergic neurons. The Journal of biological chemistry 18 16204240
2024 Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons. Proceedings of the National Academy of Sciences of the United States of America 17 38805282
2022 Characterisation of deep dorsal horn projection neurons in the spinal cord of the Phox2a::Cre mouse line. Molecular pain 16 36000342
2005 The cAMP pathway in combination with BMP2 regulates Phox2a transcription via cAMP response element binding sites. The Journal of biological chemistry 16 16330553
2004 ARIX gene polymorphisms in patients with congenital superior oblique muscle palsy. The British journal of ophthalmology 16 14736788
2009 Time-dependent activation of Phox2a by the cyclic AMP pathway modulates onset and duration of p27Kip1 transcription. Molecular and cellular biology 14 19564421
2008 The expression of PHOX2A, PHOX2B and of their target gene dopamine-beta-hydroxylase (DbetaH) is not modified by exposure to extremely-low-frequency electromagnetic field (ELF-EMF) in a human neuronal model. Toxicology in vitro : an international journal published in association with BIBRA 12 18572378
2016 PHOX2A and PHOX2B are differentially regulated during retinoic acid-driven differentiation of SK-N-BE(2)C neuroblastoma cell line. Experimental cell research 11 26902400
2005 ARIX and PHOX2B polymorphisms in patients with congenital superior oblique muscle palsy. Acta medica Okayama 11 16049556
2004 Characterization of Xenopus Phox2a and Phox2b defines expression domains within the embryonic nervous system and early heart field. Gene expression patterns : GEP 11 15261839
2008 Clinical features, ARIX and PHOX2B nucleotide changes in three families with congenital superior oblique muscle palsy. Acta medica Okayama 9 18323871
2005 ERK1/2 is a negative regulator of homeodomain protein Arix/Phox2a. Journal of neurochemistry 9 16156742
2007 Abnormal inspiratory depth in Phox2a haploinsufficient mice. Neuroscience 7 17218061
2020 Transcription Factors Phox2a/2b Upregulate Expression of Noradrenergic and Dopaminergic Phenotypes in Aged Rat Brains. Neurotoxicity research 6 32617854
1996 Mapping of the ARIX homeodomain gene to mouse chromosome 7 and human chromosome 11q13. Genomics 6 8661014
2023 Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons. bioRxiv : the preprint server for biology 5 37786726
2004 Ciliary neurotrophic factor suppresses Phox2a in sympathetic neurons. Neuroreport 4 15106827
2023 Prdm12 represses the expression of the visceral neuron determinants Phox2a/b in developing somatosensory ganglia. iScience 2 38025786
2022 Somatotopy of Mouse Spinothalamic Innervation and the Localization of a Noxious Stimulus Requires Deleted in Colorectal Carcinoma Expression by Phox2a Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 2 36028316
2012 [Identification of a novel PHOX2A gene mutation in a Chinese family with congenital fibrosis of extraocular muscles type 2]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 22311481
2025 Phox2a in Lateral Spinal Nucleus Tac1-Positive Neurons Mediates Histamine-Independent Acute Itch. CNS neuroscience & therapeutics 1 41204431
2025 Epigenetic modifications of the PHOX2A and CDH2 genes expression- new insights into the pathogenesis of multiple myeloma. BMC cancer 0 41146049

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