Affinage

PHOX2A

Paired mesoderm homeobox protein 2A · UniProt O14813

Length
284 aa
Mass
29.7 kDa
Annotated
2026-04-28
55 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PHOX2A is a paired-like homeodomain transcription factor that serves as a master regulator of autonomic and cranial motor neuron identity, governing the development of the locus coeruleus, sympathetic and parasympathetic ganglia, oculomotor/trochlear nuclei, and spinal nociceptive relay neurons. It directly binds multiple homeodomain sites in target promoters—including DBH, p27(Kip1), TLX2, and CHRNA3—to activate transcription of noradrenergic, cell-cycle exit, and neuronal subtype genes, acting downstream of MASH1/BMP2 signaling and upstream of c-RET in the autonomic differentiation cascade (PMID:9763470, PMID:9435282, PMID:16982676, PMID:17344216). Its DNA-binding activity is controlled by sequential phosphoregulation: constitutive phosphorylation (including ERK1/2-mediated N-terminal phosphorylation) inhibits DNA binding, while cAMP/PKA-driven dephosphorylation of Ser206 activates it, followed by PKA phosphorylation of Ser153 that terminates transcription, creating a built-in temporal switch (PMID:19564421, PMID:16156742, PMID:11943777). Homozygous loss-of-function mutations in PHOX2A cause congenital fibrosis of the extraocular muscles type 2 (CFEOM2) in humans (PMID:11600883).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    Establishing PHOX2A as essential for autonomic neuron survival and noradrenergic identity resolved the question of whether a single transcription factor could specify both cell fate and neurotransmitter phenotype in the peripheral and central autonomic nervous system.

    Evidence Targeted gene deletion in mice showing loss of locus coeruleus, cranial sensory ganglia, and DBH/Ret expression with massive apoptosis

    PMID:9115735 PMID:9374403

    Open questions at the time
    • Mechanism by which Phox2a prevents apoptosis not determined
    • Extent of redundancy with Phox2b in different ganglionic populations unresolved
  2. 1997 High

    Demonstrating synergy between Phox2a and cAMP/PKA signaling on the DBH promoter established that Phox2a does not act alone but requires second-messenger input to activate noradrenergic transcription.

    Evidence Transient transfection reporter assays in non-neuronal cells with dominant-negative CREB and EMSA

    PMID:9341190

    Open questions at the time
    • Identity of the kinase/phosphatase mediating cAMP effect on Phox2a was unknown at this stage
  3. 1998 High

    Placing Phox2a downstream of MASH1 and BMP2, and upstream of c-RET, defined the core transcription factor cascade for autonomic neuronal identity specification from neural crest stem cells.

    Evidence Mash1 knockout mice lacking Phox2a expression; retroviral gain-of-function in neural crest stem cells showing MASH1→Phox2a→c-RET hierarchy

    PMID:9435281 PMID:9435282

    Open questions at the time
    • Whether MASH1 directly or indirectly activates Phox2a transcription was not resolved
    • Parallel or compensatory pathways between Phox2a and Phox2b not fully delineated
  4. 1998 High

    Mapping multiple homeodomain binding sites in the DBH promoter and demonstrating cooperative, Sp1/AP2-dependent synergistic activation revealed how Phox2a achieves robust cell-type-specific transcription through combinatorial promoter architecture.

    Evidence EMSA, Southwestern analysis, mutant DBH reporter constructs, and cotransfection in DBH-negative cell lines

    PMID:9763470 PMID:9798905

    Open questions at the time
    • Structural basis for cooperative DNA binding not determined
    • Whether Phox2a binds as monomer vs. dimer at each site was only later clarified
  5. 1999 High

    Zebrafish soulless mutant confirmed cross-species conservation of Phox2a function in locus coeruleus specification and added FGF8 and BMP concentration as upstream positional signals, linking patterning to fate.

    Evidence Zebrafish loss- and gain-of-function with epistasis to FGF8/BMP signaling

    PMID:10595509

    Open questions at the time
    • Direct transcriptional targets of Phox2a in zebrafish LC neurons not identified
  6. 2000 High

    Identifying the N-terminal activation domain–CBP interaction and Phox2a self-association (multimerization) explained how Phox2a integrates PKA signaling via a coactivator and achieves cooperative promoter occupancy.

    Evidence Mammalian one- and two-hybrid systems, domain mutational analysis, protein interaction assays

    PMID:10644760 PMID:11034547

    Open questions at the time
    • Crystal structure of Phox2a–CBP interaction not available
    • Stoichiometry of multimer on native promoters undetermined
  7. 2001 High

    Discovery that PHOX2A mutations cause CFEOM2 in humans established a direct disease link and confirmed PHOX2A is indispensable for oculomotor/trochlear motor nucleus development.

    Evidence Sequencing of CFEOM2 pedigrees identifying three homozygous mutations

    PMID:11600883

    Open questions at the time
    • Whether CFEOM2 mutations affect protein stability, DNA binding, or cofactor interaction was not fully dissected
    • Phox2b direct regulation of Phox2a transcription shown same year but functional interplay in disease context unexplored
  8. 2002 High

    Demonstrating that Phox2a is constitutively phosphorylated and that PKA-induced dephosphorylation activates DNA binding provided the first direct link between post-translational modification and Phox2a transcriptional competence.

    Evidence In vivo phosphorylation analysis, phosphatase inhibitors, DNA binding assays, DBH reporter assays

    PMID:11943777 PMID:11948255

    Open questions at the time
    • Identity of the specific phosphorylation sites was not yet mapped
    • The relevant phosphatase was not identified
  9. 2005 High

    Identification of ERK1/2 as an inhibitory kinase and CREB as a direct activator of Phox2a transcription revealed that Phox2a integrates opposing MAPK and cAMP signals at both the transcriptional and post-translational levels.

    Evidence In vitro kinase assays, MEK inhibitors in sympathetic neurons, ChIP showing CREB/CBP on Phox2a promoter CRE elements

    PMID:16156742 PMID:16204240 PMID:16330553

    Open questions at the time
    • ERK1/2 phosphorylation sites within the N-terminal domain were mapped but individual site contributions not fully separated from Ser206/Ser153 PKA axis
  10. 2006 High

    Showing that Phox2a directly activates p27(Kip1) transcription via homeodomain elements linked Phox2a to cell cycle exit, establishing it as a coordinator of differentiation and proliferative arrest in neural progenitors.

    Evidence ChIP demonstrating in vivo binding to p27 promoter, siRNA knockdown, inducible overexpression in neural crest cells

    PMID:16982676

    Open questions at the time
    • Whether p27 is required for all Phox2a-driven differentiation or only specific lineages not tested
  11. 2007 High

    Discovery that PHOX2A regulates CHRNA3 through Sp1 protein–protein interaction without direct DNA binding expanded the mechanistic repertoire of PHOX2A beyond canonical homeodomain–DNA interactions.

    Evidence ChIP, DNA pulldown, co-immunoprecipitation with Sp1, cotransfection with homeodomain-deletion mutants

    PMID:17344216

    Open questions at the time
    • Structural basis for Phox2a–Sp1 interaction unknown
    • Whether this DNA-independent mechanism applies to other target genes not explored
  12. 2009 High

    Mass spectrometry identification of Ser206 and Ser153 as sequential phosphoswitches provided a molecular clock model: dephosphorylation of Ser206 initiates DNA binding, then PKA phosphorylation of Ser153 terminates it, explaining how a single cAMP pulse generates a transient transcriptional burst.

    Evidence Mass spectrometry, phosphospecific antibodies, Ser-to-Ala/Asp mutants in inducible cell lines, in vitro DNA binding

    PMID:19564421

    Open questions at the time
    • In vivo temporal dynamics of the phosphoswitch not visualized in real time
    • Whether the same sequential mechanism operates in all Phox2a-expressing cell types unknown
  13. 2010 High

    Forced expression of PHOX2A in chick midbrain drove a complete oculomotor program including motor nerve outgrowth and correct nucleogenesis, demonstrating sufficiency of a single transcription factor for both cell fate specification and spatial organization of a cranial motor nucleus.

    Evidence In ovo electroporation in chick, immunohistochemistry, nerve tracing

    PMID:20215354

    Open questions at the time
    • Whether Phox2a also controls axon guidance molecules directly or indirectly not resolved
  14. 2020 High

    Lineage tracing revealed that Phox2a marks anterolateral system nociceptive relay neurons projecting to the parabrachial nucleus and thalamus, extending PHOX2A's role from autonomic/motor specification to somatosensory circuit development.

    Evidence Phox2a::Cre lineage tracing with retrograde labeling and developmental analysis in mouse and human fetal spinal cord

    PMID:33238113

    Open questions at the time
    • Direct transcriptional targets of Phox2a in spinal relay neurons not identified
    • Whether Phox2a is required for maintenance or only initial specification of these neurons unknown
  15. 2022 High

    Conditional deletion of Dcc in Phox2a neurons impaired somatotopic map formation in the thalamus, establishing that Phox2a-lineage neurons require DCC-netrin signaling for topographic axon targeting underlying body-region localization of pain.

    Evidence Conditional Dcc knockout in Phox2a neurons, anatomical tracing, behavioral topognosis assays

    PMID:36028316

    Open questions at the time
    • Whether Phox2a directly regulates Dcc expression not tested
    • Role of other guidance cues in Phox2a neuron targeting not examined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for Phox2a cooperative DNA binding and cofactor assembly, the complete set of direct transcriptional targets in each neuronal lineage, whether the Ser206/Ser153 phosphoswitch operates uniformly across all Phox2a-expressing populations, and the extent of functional redundancy versus unique roles relative to Phox2b.
  • No crystal or cryo-EM structure of Phox2a homeodomain–DNA complex available
  • Genome-wide direct target identification (e.g., ChIP-seq) in primary neurons lacking
  • Phosphoswitch dynamics not validated in vivo across lineages

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 9 GO:0140110 transcription regulator activity 8
Localization
GO:0005634 nucleus 6
Pathway
R-HSA-1266738 Developmental Biology 7 R-HSA-74160 Gene expression (Transcription) 7 R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 4
Partners
ASCL1CBPCREB1HAND2PHOX2BSP1

Evidence

Reading pass · 31 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 cranial sensory ganglia (VIIth, IXth, Xth); in sensory ganglia, Phox2a controls noradrenergic traits (dopamine-beta-hydroxylase transient expression) and regulates Ret expression, with loss leading to massive apoptosis of ganglion cells. Targeted gene deletion (knockout mice), immunohistochemistry, genetic loss-of-function Neuron High 9115735
1997 Phox2a and Phox2b are co-expressed at most autonomic nervous system sites; Phox2b expression in cranial ganglia is lost in Phox2a-deficient mice, indicating positive cross-regulation between the two Phox2 genes. Knockout mice analysis, in situ hybridization, immunohistochemistry Development High 9374403
1997 Arix/Phox2a interacts synergistically with cAMP/PKA signaling to activate the dopamine beta-hydroxylase (DBH) promoter; neither Arix alone nor cAMP alone effectively stimulates DBH transcription in non-neuronal cells, but together they substantially activate it; CREB, CREM, Fos, and Jun interact with the DB1 regulatory element adjacent to the Arix binding site. Transient transfection reporter assays, dominant-negative CREB, EMSA, antisera supershift Journal of Biological Chemistry High 9341190
1998 MASH1 controls expression of Phox2a in noradrenergic centers of the brain and peripheral autonomic ganglia; in Mash1-/- mutants, Phox2a expression is abolished or massively altered, placing MASH1 upstream of Phox2a in the noradrenergic differentiation cascade. Targeted Mash1 knockout mice, in situ hybridization, immunohistochemistry Development High 9435281 9435282
1998 BMP2 induces Phox2a expression in neural crest stem cells; constitutive expression of MASH1 induces Phox2a and c-RET; constitutive Phox2a expression induces c-RET but not pan-neuronal markers, placing Phox2a downstream of MASH1 and upstream of c-RET in autonomic neuronal identity specification. Retroviral gain-of-function in neural crest stem cells, loss-of-function in Mash1-/- mice, colony assays Development High 9435282
1998 Phox2a (and Phox2b) bind to a homeodomain (HD)-binding site within the DBH promoter domain IV in a noradrenergic cell-specific manner and robustly activate DBH promoter activity in DBH-negative cell lines; neither activates tyrosine hydroxylase transcription, demonstrating selectivity for noradrenergic target genes. Transient transfection reporter assays, EMSA, forced expression in DBH-negative cell lines Journal of Neurochemistry High 9798905
1998 Phox2a binds at least two sites in the DBH proximal promoter (domain II and within domain IV); synergistic activation of DBH transcription requires cooperation between at least two Phox2a-binding sites plus Sp1 and AP2 sites; four tandem copies of domain II increased minimal DBH promoter activity 100-200 fold in a Phox2a-dependent, cell-specific manner. Transient transfection with mutant DBH reporter constructs, EMSA, Southwestern analysis, competition and antibody supershift assays, cotransfection Journal of Neuroscience High 9763470
1999 In zebrafish, Phox2a (soulless) is necessary and sufficient for locus coeruleus noradrenergic neuron development; Phox2a can induce Phox2b expression and ectopic NA neurons; its expression in LC progenitors requires FGF8 from the mid/hindbrain boundary and optimal BMP signal concentrations. Zebrafish genetic mutant (soulless), ectopic overexpression, epistasis with FGF8/BMP signaling pathways Neuron High 10595509
1999 Forced expression of Phox2a does not affect human norepinephrine transporter (hNET) promoter activity in NET-negative cells, in contrast to its robust activation of the DBH promoter, demonstrating that Phox2a selectively regulates DBH but not NET through distinct molecular mechanisms. Transient transfection reporter assays, primer extension, 5'-RACE Journal of Biological Chemistry Medium 10037744
2000 Arix/Phox2a activates DBH transcription through multiple homeodomain binding sites, all of which are essential for basal and PKA-stimulated transcription; intracellular Arix-Arix interactions occur and contribute to site interdependence; the N-terminal activation domain of Arix interacts with CBP (CREB-binding protein) coactivator to potentiate PKA-dependent transcription; Arix also has a C-terminal repression domain. Mammalian one- and two-hybrid systems, transfection reporter assays, domain mutational analysis, protein interaction assays Journal of Biological Chemistry High 10644760
2000 Both Arix/Phox2a and NBPhox/Phox2b bind to three sites in the rat DBH promoter, form DNA-independent multimers, and exhibit cooperative binding to the DB1 element; when coexpressed, their transcriptional stimulation is non-additive (~equal to either alone), demonstrating independent but non-redundant mechanisms. In vitro DNA binding assays, transfection reporter assays, coexpression experiments DNA and Cell Biology Medium 11034547
2001 Phox2b directly binds to a homeodomain recognition site in the 5' regulatory region of the human Phox2a gene (shown by EMSA) and transactivates the Phox2a promoter (shown by cotransfection), providing the first molecular evidence that Phox2b directly regulates Phox2a expression. EMSA, cotransfection reporter assays, promoter deletion analysis Journal of Neuroscience High 11549713
2001 Three homozygous mutations in PHOX2A (two predicted to disrupt splicing; one altering an amino acid in the brachyury-like domain) cause congenital fibrosis of extraocular muscles type 2 (CFEOM2), confirming PHOX2A as essential for oculomotor (nIII) and trochlear (nIV) cranial nerve nucleus development in humans. Human genetic mutation analysis (sequencing of CFEOM2 pedigrees), functional domain mapping Nature Genetics High 11600883
2002 Single point mutations in the Phox2a homeodomain abolish transactivation of the DBH promoter in vitro and cause loss of noradrenergic neurons in vivo (zebrafish antisense experiments); Phox2a binds DBH promoter as monomer at PBD1 and as dimer at PBD2/PBD3; mutations in 3-4 (but not 1-2) binding sites abolish DBH activation. In vitro transactivation assays with homeodomain point mutants, antisense oligonucleotide injection in zebrafish, EMSA with monomeric/dimeric forms Journal of Neurochemistry High 11948255
2002 Arix/Phox2a is constitutively phosphorylated in vivo; PKA pathway activation causes dephosphorylation of Arix, which coincides with increased DNA binding activity and DBH transcriptional activation; phosphatase inhibitors reverse this effect, demonstrating that dephosphorylation is required for PKA-mediated DBH transcription. In vivo phosphorylation analysis, DNA binding assays, transcription reporter assays, pharmacological treatments (forskolin, phosphatase inhibitors), amino acid analysis (phosphoserine) Journal of Biological Chemistry High 11943777
2003 HAND2 (dHAND) synergistically enhances Phox2a-driven transcription at the DBH promoter; this synergy requires Phox2a homeodomain binding sites but not direct HAND2 DNA binding; HAND2 interaction with CBP is required for synergistic activation; Arix/Phox2a coprecipitates with anti-dHAND antisera confirming direct protein-protein interaction. Cotransfection reporter assays, site-directed mutagenesis of promoter elements, co-immunoprecipitation, EMSA Journal of Biological Chemistry / Developmental Biology High 14506227 14512028
2004 Loss of Phox2a in mice abolishes A6 (locus coeruleus) noradrenergic neuron development; A6 neurons are connected to the neonatal respiratory network (shown by rabies virus transsynaptic tracing); Phox2a-/- mice exhibit impaired respiratory activity that can be phenocopied by pharmacological blockade of alpha1 adrenoceptors during gestation, establishing a pathway from Phox2a → A6 neurons → noradrenaline → alpha1 adrenoceptor signaling → respiratory rhythm maturation. Phox2a-/- mice, rabies virus transsynaptic tracing, pharmacological blockade (prazosin), in vivo/in vitro respiratory recordings Journal of Neuroscience High 14749437
2005 The cAMP pathway has dual inputs on Phox2a: it regulates both Phox2a transcription (via CREB-mediated mechanism requiring PKA) and Phox2a activity (via dephosphorylation); PKA inhibition or PP2A-like phosphatase inhibition with okadaic acid suppresses Phox2a dephosphorylation, DNA binding, and DBH reporter expression, establishing that Phox2a dephosphorylation is required for its activation. Primary neural crest cultures, dominant-negative CREB, pharmacological inhibitors (H89, okadaic acid), in vitro DNA binding, reporter assays Journal of Biological Chemistry High 16204240
2005 The Phox2a promoter contains two CRE half-sites at ~-5.5 kb (conserved in mouse and human) that are occupied by CREB and CBP in vivo; a 170-bp region proximal to these CREs containing E-box and CCAAT sites confers synergistic BMP2+cAMP regulation; CREB directly activates Phox2a transcription via these elements. Chromatin immunoprecipitation (ChIP), transient transfection of reporter constructs, histone deacetylase inhibitor treatment Journal of Biological Chemistry High 16330553
2005 Arix/Phox2a is phosphorylated by ERK1/2 at two sites within the N-terminal transactivation domain; ERK1/2-mediated phosphorylation inhibits Arix interaction with DBH and NET (but not TH) target genes; MEK1 inhibition reduces Arix phosphorylation and elevates DBH and NET mRNAs in sympathetic neurons. In vitro kinase assays, MEK1 inhibitors (UO126, PD98059), chromatin interaction assays, mRNA quantification in sympathetic neurons Journal of Neurochemistry High 16156742
2006 Phox2a, activated by cAMP/BMP2 signaling, directly binds homeodomain cis-acting elements in the p27(Kip1) promoter in vivo and induces p27(Kip1) transcription; siRNA silencing of Phox2a suppresses p27(Kip1) transcription and neuronal differentiation; ectopic Phox2a promotes accelerated differentiation and p27(Kip1) transcription only in the presence of cAMP, establishing Phox2a as a coordinator of neural progenitor cell cycle exit and differentiation. siRNA knockdown, Tet-off ectopic expression, ChIP, luciferase reporter assays, primary neural crest cells and CAD cell line Molecular and Cellular Biology High 16982676
2007 PHOX2A regulates the human alpha3 nicotinic acetylcholine receptor subunit gene (CHRNA3) promoter; PHOX2A assembles on the SacI-NcoI region of the alpha3 promoter (shown by ChIP and DNA pulldown); it does not appear to bind DNA directly (homeodomain dispensable for regulation) but interacts with Sp1 via direct or indirect protein-protein interactions (shown by co-immunoprecipitation), regulating alpha3 transcription through a DNA-independent mechanism. Chromatin immunoprecipitation (ChIP), DNA pulldown assay, cotransfection reporter assays, co-immunoprecipitation Journal of Biological Chemistry High 17344216
2007 PHOX2A directly transactivates the TLX2 gene; PHOX2A, like PHOX2B, binds TLX2 regulatory sequences (shown by EMSA and ChIP) and activates TLX2 transcription (shown by cotransfection), placing PHOX2A in a cascade leading to intestinal neuronal differentiation. Cotransfection reporter assays, EMSA, chromatin immunoprecipitation (ChIP) European Journal of Human Genetics Medium 17505528
2009 cAMP-dependent activation of Phox2a involves two sequential phosphorylation events: first, dephosphorylation of Ser206 (identified by mass spectrometry) allows Phox2a to bind DNA and initiate p27(Kip1) transcription; second, PKA phosphorylates Ser153 (after dephosphorylation of Ser202/Ser208), preventing DNA association and terminating transcription—providing a built-in temporal switch within the same cAMP signal. Mass spectrometry phosphosite identification, phosphospecific antibodies, serine-to-alanine/aspartate mutants in inducible cell lines, in vitro DNA binding assays Molecular and Cellular Biology High 19564421
2010 In chick midbrain, forced expression of PHOX2A drives a complete oculomotor complex (OMC) molecular program including both visceral and somatic motoneuron production, generates ectopic motor nerves that directly innervate extraocular muscle, and directs ectopic neurons to their correct native spatial positions, demonstrating that a single transcription factor can both specify motoneuron cell fates and orchestrate spatially organized nucleogenesis. In ovo forced expression (chick electroporation), immunohistochemistry, nerve tracing Development High 20215354
2011 Lmx1b regulates Phox2a expression and the sequential specification of ocular motor neurons and red nucleus neurons from progenitors lateral to dopamine neurons in the midbrain; Phox2a expression is lost in Lmx1b mutants, placing Lmx1b upstream of Phox2a in midbrain motor neuron specification. Lmx1b conditional knockout mice, in situ hybridization, immunohistochemistry Development High 21752929
2020 Most spinal neurons that embryonically express Phox2a innervate nociceptive brain targets (parabrachial nucleus and thalamus); Phox2a plays an essential role in the development of nociceptive relay neurons (anterolateral system neurons), and the molecular identity of Phox2a neurons is conserved in the human fetal spinal cord. Phox2a::Cre lineage tracing, retrograde labeling, immunohistochemistry, developmental analysis of birth order/migration Cell Reports High 33238113
2022 Deletion of Dcc (netrin-1 receptor) specifically in Phox2a neurons impairs topognosis (rostrocaudal localization of noxious stimuli) and causes defective targeting of cervical and lumbar anterolateral system axons within the thalamus, establishing that DCC-netrin signaling in Phox2a neurons is required for somatotopic map formation. Conditional Dcc knockout in Phox2a neurons, anatomical tracing, behavioral assays Journal of Neuroscience High 36028316
2023 Prdm12 is required in somatosensory neural precursors to repress Phox2a and Phox2b expression; loss of Prdm12 leads to ectopic Phox2a/Phox2b expression in dorsal root and trigeminal ganglia, suggesting Prdm12 prevents nociceptor precursors from adopting a Phox2-driven visceral neuronal fate. Prdm12 knockout mouse model, immunohistochemistry, in situ hybridization, transcriptomic analysis iScience Medium 38025786
2024 A PHOX2A variant (p.Trp137Cys) shows reduced or abolished DNA binding in protein binding microarray assays, establishing that Trp137 within the homeodomain is critical for DNA binding activity of PHOX2A. Protein binding microarrays, zebrafish G0 CRISPR/Cas9 knockout phenotypic screen bioRxiv (preprint)preprint Medium
2025 Phox2a is expressed in LSN Tac1-positive neurons and is downregulated during chloroquine-induced histamine-independent itch; overexpression of Phox2a in LSNTac1 neurons suppresses scratching behavior and reduces sEPSC amplitude without changing frequency, indicating Phox2a modulates histamine-independent itch via presynaptic excitability regulation. Chemogenetic activation/inhibition, whole-cell patch-clamp, viral-mediated overexpression, immunohistochemistry, FISH, behavioral assays CNS Neuroscience & Therapeutics Medium 41204431

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) 489 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 165 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) 104 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 85 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 49 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
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
2021 Characterisation of lamina I anterolateral system neurons that express Cre in a Phox2a-Cre mouse line. Scientific reports 17 34504158
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
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 15 38805282
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 4 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