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Gene Review

Phox2a  -  paired-like homeobox 2a

Mus musculus

Synonyms: Aristaless homeobox protein homolog, Arix, PHOX2A homeodomain protein, Paired mesoderm homeobox protein 2A, Paired-like homeobox 2A, ...
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Disease relevance of Phox2a


High impact information on Phox2a

  • In the previous study, the targeting construct left the first eighteen exons encoding Inppl1 intact, generating a Inppl1(EX19-28-/-) mouse, and apparently also deleted a second gene, Phox2a [4].
  • Interestingly, the homeobox gene Phox2a is activated independently of ngn2 in epibranchial placodes, suggesting that neuronal fate and neuronal subtype identity may be specified independently in cranial sensory ganglia [5].
  • First, the transient expression of dopamine-beta-hydroxylase in neuroblasts is abolished, providing evidence that Phox2a controls noradrenergic traits in vivo [6].
  • In the sensory ganglia, we have identified two differentiation blocks in Phox2a-/- mice [6].
  • Defects in sensory and autonomic ganglia and absence of locus coeruleus in mice deficient for the homeobox gene Phox2a [6].

Biological context of Phox2a


Anatomical context of Phox2a

  • We had previously characterized the homeobox gene Phox2a, which is expressed in differentiating neurons of the central and peripheral autonomic nervous system as well as in motor nuclei of the hindbrain [10].
  • In the major part of the rhombencephalon, Phox2b expression precedes that of Phox2a and starts in the proliferative neuroepithelium, in a pattern strikingly restricted on the dorsoventral axis and at rhombomeric borders [10].
  • Targeted deletion of the Phox2a gene affects part of the structures in which it is expressed: the locus coeruleus, visceral sensory and parasympathetic ganglia and, as we show here, the nuclei of the IIIrd and IVth cranial nerves [10].
  • Our previous results have shown that Phox2a controls the differentiation of the main noradrenergic center of the brain, the locus coeruleus, but leaves unaffected the other noradrenergic centers [11].
  • Furthermore, we demonstrate unique roles of Phox2 genes in the differentiation of specific motor neurons [7].

Associations of Phox2a with chemical compounds

  • 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 [12].
  • In Phox2a mutant mice, which do not express A6 neurons, we previously hypothesized that the release of endogenous norepinephrine by A6 neurons is required for a normal respiratory rhythm to occur at birth [13].
  • Fourth, blocking the alpha1 adrenoceptors in wild-type dams during late gestation with daily injections of the alpha1 adrenoceptor antagonist prazosin induced in vivo and in vitro neonatal respiratory deficits similar to those observed in Phox2a mutants [3].

Physical interactions of Phox2a

  • We discuss the nonredundancy of Phox2 genes and their complex partnership with the bHLH transcription factor Mash1, which is also required for the differentiation of most noradrenergic cell types [11].

Regulatory relationships of Phox2a

  • In both mouse and chicken, LoC neurons first appear arranged linearly along the middle one-third of the alar plate of rhombomere 1 (r1), collinear to a reference ventricular longitudinal band that early on expresses Phox2a and Phox2b in the alar plate of r2 and later expands to r1 [14].
  • Another SHIP2 knockout mouse has now been generated which inactivates the SHIP2 gene but leaves Phox2a intact [2].
  • We have provided the first molecular evidence that Phox2b can regulate the expression of Phox2a by directly binding to its 5' regulatory region [15].

Other interactions of Phox2a

  • The closely related homeobox genes Phox2a and Phox2b are expressed in all central and peripheral noradrenergic neurons [11].
  • Nitric oxide synthase (NOS) neurons showed Phox2b and Ret immunoreactivity at all ages, and Phox2a and p75(NTR) immunoreactivity only transiently [12].
  • Calcitonin gene-related peptide (CGRP) neurons showed Phox2b and Ret-immunoreactivity, but not Phox2a immunoreactivity [12].
  • The mutant epibranchial progenitor cells fail to express Neurog2 that is required for the determination of neuronal precursors, and other basic helix-loop-helix as well as the paired homeobox Phox2 genes that are essential for neural differentiation and maintenance [16].
  • Notably, activated Acvr1 signalling gave significantly lower TBI-induced up-regulations of Gfap and Phox2a mRNA levels, indicating reductions in astroglial and neuronal reactions to injury [17].


  1. Role of the target in the pathfinding of facial visceral motor axons. Jacob, J., Tiveron, M.C., Brunet, J.F., Guthrie, S. Mol. Cell. Neurosci. (2000) [Pubmed]
  2. The SH2 domain containing inositol polyphosphate 5-phosphatase-2: SHIP2. Dyson, J.M., Kong, A.M., Wiradjaja, F., Astle, M.V., Gurung, R., Mitchell, C.A. Int. J. Biochem. Cell Biol. (2005) [Pubmed]
  3. Phox2a gene, A6 neurons, and noradrenaline are essential for development of normal respiratory rhythm in mice. Viemari, J.C., Bévengut, M., Burnet, H., Coulon, P., Pequignot, J.M., Tiveron, M.C., Hilaire, G. J. Neurosci. (2004) [Pubmed]
  4. Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity. Sleeman, M.W., Wortley, K.E., Lai, K.M., Gowen, L.C., Kintner, J., Kline, W.O., Garcia, K., Stitt, T.N., Yancopoulos, G.D., Wiegand, S.J., Glass, D.J. Nat. Med. (2005) [Pubmed]
  5. The bHLH protein NEUROGENIN 2 is a determination factor for epibranchial placode-derived sensory neurons. Fode, C., Gradwohl, G., Morin, X., Dierich, A., LeMeur, M., Goridis, C., Guillemot, F. Neuron (1998) [Pubmed]
  6. Defects in sensory and autonomic ganglia and absence of locus coeruleus in mice deficient for the homeobox gene Phox2a. Morin, X., Cremer, H., Hirsch, M.R., Kapur, R.P., Goridis, C., Brunet, J.F. Neuron (1997) [Pubmed]
  7. Reciprocal gene replacements reveal unique functions for Phox2 genes during neural differentiation. Coppola, E., Pattyn, A., Guthrie, S.C., Goridis, C., Studer, M. EMBO J. (2005) [Pubmed]
  8. Paired-like homeodomain proteins Phox2a/Arix and Phox2b/NBPhox have similar genetic organization and independently regulate dopamine beta-hydroxylase gene transcription. Adachi, M., Browne, D., Lewis, E.J. DNA Cell Biol. (2000) [Pubmed]
  9. The cAMP pathway in combination with BMP2 regulates Phox2a transcription via cAMP response element binding sites. Benjanirut, C., Paris, M., Wang, W.H., Hong, S.J., Kim, K.S., Hullinger, R.L., Andrisani, O.M. J. Biol. Chem. (2006) [Pubmed]
  10. Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis. Pattyn, A., Morin, X., Cremer, H., Goridis, C., Brunet, J.F. Development (1997) [Pubmed]
  11. Specification of the central noradrenergic phenotype by the homeobox gene Phox2b. Pattyn, A., Goridis, C., Brunet, J.F. Mol. Cell. Neurosci. (2000) [Pubmed]
  12. 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. Young, H.M., Ciampoli, D., Hsuan, J., Canty, A.J. Dev. Dyn. (1999) [Pubmed]
  13. Ret deficiency in mice impairs the development of A5 and A6 neurons and the functional maturation of the respiratory rhythm. Viemari, J.C., Maussion, G., Bévengut, M., Burnet, H., Pequignot, J.M., Népote, V., Pachnis, V., Simonneau, M., Hilaire, G. Eur. J. Neurosci. (2005) [Pubmed]
  14. Locus coeruleus neurons originate in alar rhombomere 1 and migrate into the basal plate: Studies in chick and mouse embryos. Aroca, P., Lorente-Cánovas, B., Mateos, F.R., Puelles, L. J. Comp. Neurol. (2006) [Pubmed]
  15. Sp proteins and Phox2b regulate the expression of the human Phox2a gene. Flora, A., Lucchetti, H., Benfante, R., Goridis, C., Clementi, F., Fornasari, D. J. Neurosci. (2001) [Pubmed]
  16. Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes. Zou, D., Silvius, D., Fritzsch, B., Xu, P.X. Development (2004) [Pubmed]
  17. Genetically modified bone morphogenetic protein signalling alters traumatic brain injury-induced gene expression responses in the adult mouse. Israelsson, C., Lewén, A., Kylberg, A., Usoskin, D., Althini, S., Lindeberg, J., Deng, C.X., Fukuda, T., Wang, Y., Kaartinen, V., Mishina, Y., Hillered, L., Ebendal, T. J. Neurosci. Res. (2006) [Pubmed]
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