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Paired-like Homeobox 2a (Gene PHOX2A)The human PHOX2A (map locus: Entrez: 11a13.2: Ensembl/HGNC: 11q13.4) gene product, paired-like homeobox 2A, is a 284 AA (29.6 kDa) protein that contains a 60 AA (90-149) DNA-binding helix-turn-helix (HTH) homeobox. Phox2a and phox2b are paralogues with identical homeobox domains. However, the paralogues are not functionally equivalent. Phox2b can replace Phox2a in structures that depend on both genes, but 2a cannot always replace 2b, Coppola E, et al. (2005). Phox2a plays a critical role in the development of the autonomic nervous system (ANS), wherein it promotes the differentiation of dopaminergic and noradrenergic neurons. Phox2a is expressed in differentiating neurons of the central and peripheral autonomic nervous system and motor nuclei of the hindbrain, Pattyn A et al. (1997). Phox2a is essential for proper development of the locus coeruleus, visceral sensory ganglia (adrenergic), a subset of sympathetic and parasympathetic (noradrenergic) ganglia and the IIIrd, IVth, VIIth, IXth, and Xth cranial sensory ganglia, Morin X, et al. (1997), Pattyn A et al. (1997). The locus coeruleus (LC) is the major noradrenergic center of the brain. The LC neurons originate in the alar plate of rhombomere 1 and migrate into the basal plate, Aroca P, et al. (2006). Development of the LC requires initial BMP-dependent expression of Phox2a and Phox2b in dorsal rhombomere1 (r1), Vogel-Höpker A and Rohrer H. (2002). The transformation of LC neurons into noradrenergic neurons involves the expression of two catecholaminergic enzymes, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), the terminal enzyme for noradrenaline biosynthesis. Phox2a/Arix is expressed in noradrenergic, DBH-positive tissues and regulates the transcription of TH and DBH in neural crest-derived noradrenergic neurons (sympatho-adrenergic cells), Zellmer E, et al. (1995); Yang C, et al. (1998); Lo L, et al. (1999); Seo H, et al. (2002); and Stanke M, et al. (1999). The induction of DBH expression by Phox2a/Arix is enhanced by direct protein-protein interaction with HAND2, Rychlik JL, et al. (2003) and interaction between HAND2 and CBP (cAMP response element binding protein), Xu H, et al. (2003) in the transcription complex. Hand2 plays a major role in the induction of the noradrenalin phenotype, Morikawa Y, et al. (2007). Phox2a regulates transcription of human alpha3 nicotinic acetylcholine receptor gene, which encodes the ligand-binding subunit of the ganglionic type nicotinic receptor. The alpha3 subunit is expressed in every terminally differentiated ganglionic cell; this is the first example of a "pan-autonomic" gene whose expression is regulated by PHOX2 proteins, Benfante R, et al. (2007). Phox2a mutations have been linked to autosomal recessive congenital fibrosis of the extraocular muscles (CFEOM2; MIM: 602078), Wang SM, et al. (1998); Yazdani A, et al. (2003), reviewed by Heidary G, et al. (2008). CFEOM2 is a strabismus syndrome characterized by non-progressive, restrictive ophthalmoplegia of the extra-ocular muscles and congenital blepharoptosis and the dysinnervation of extraocular muscles supplied by the oculomotor (cranial nerve III) and/or trochlear (cranial nerve IV) nerves, Bosley TM et al. (2006). Sigma offers antibodies, shRNAs and other products useful for the study of the PHOX2A. References:
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