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Paired-like Homeobox 2b (Gene PHOX2B)The human PHOX2B (map locus: Entrez: 4p12; Ensembl/HGNC: 4p13) gene product, paired-like homeobox 2b, is a 314 AA (31.6 kDa) protein that contains a 60 AA (98-157) 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). Phox2b is expressed in peripheral and central noradrenergic neurons and neural crest (NC) derivatives including the sympathetic and parasympathetic ganglia, enteric neurons, adrenal and chromaffin cells. Phox2b coordinates generic (pan-neuronal) and type-specific neuronal properties, such as differentiation of catecholaminergic (norepinephrine) phenotype, Stanke M, et al. (2004); branchio- and viscero-motoneuronal but not somatic motoneurons phenotypes, Pattyn A, et al. (2000a) and neural crest-derived autonomic ganglia, Stanke M, et al. (1999). As a pan-neuronal factor, Phox2b up-regulates proneural genes (Ngn2) and in combination with Nkx2.2, the expression of Mash1. Phoxb represses neurogenesis inhibitors Hes5 and Id2. Phox2b promotes branchiomotor subtype differentiation by repressing Pax6 and Olig2 and inducing Nkx6.1, Nkx6.2 and Islet1, Dubreuil V et al. (2002). Branchiomotor neurons are cranial neurons that innervate the branchial-arch-derived muscles of the face, jaw and neck. Phox2b controls the differentiation, migration, Coppola E, et al. (2005) and peripheral axonal phenotype (axon growth) of branchiomotor neurons, Hirsch MR, et al. (2007). Sympathetic, parasympathetic and enteric ganglia, components of the peripheral autonomic nervous system (ANS), are derived from the neural crest cells. Phox2b is essential for development of autonomic neural crest derivatives including all autonomic ganglia, Stanke M, et al. (1999). In the anlagen of the enteric nervous system and the sympathetic ganglia, Phox2b is needed for the expression of the GDNF-receptor subunit Ret and for maintaining Mash1 expression, Pattyn A, et al. (1999). Phox2b is the master regulator of all central and peripheral noradrenergic differentiation, Pattyn A et al. (2000b). Phox2b is required for biosynthesis of both tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBN) in noradrenergic neurons, Yang C, et al. (1998); Pattyn A, et al. (1999); Lo L, et al. (1999); Hong SJ et al. (2008). Serotonergic neurons found in the brainstem raphe nuclei are derived from Phox2b positive visceral motor neurons (VMN) by a Foxa2-dependent mechanism that cross-represses Phox2b expression, Jacob J, et al. (2007). Phox2b is a ‘circuit-specific’ transcription factor that controls differentiation of autonomic visceral reflex pathways (afferent relays) to geniculate, petrosal and nodose sensory ganglia and chemosensor organs such as the carotid body, Dauger S, et al. (2003). Phox2b is involved in the chemical drive circuitry and the reflex regulation of the respiratory rhythm and pattern generator (VRC and dorsolateral pons), Kang BJ, et al. (2007). Phox2b is expressed in an uninterrupted chain of neurons that integrate peripheral and central chemoreception, Stornetta RL, et al. (2006) and Geerling JC, et al. (2008). Mutations in Phox2b have been linked to congenital central hypoventilation syndrome (CCHS) (Ondine curse; OMIM 209880), especially in association with Hirschsprung's disease (HSCR) and with predisposition for a subset of neuroblastomas. CCHS is characterized by sleep apnea resulting from impaired central and peripheral chemoreflexes. Hirschsprung's disease is caused by the lack of enteric nerves (aganglionic) in the bowel that results in bowel obstruction. CCHS is caused by defects in Phox2b gene consisting mainly of alanine expansions in the poly-Ala region (241-260), Amiel J, et al. (2003); Weese-Mayer DE, et al. (2003). The Phox2b polymorphism AàG(1364) was proposed as a candidate cause of HSCR, Garcia-Barceló M, et al. (2003). The presence of CCHS together with HSCR is known as Haddad syndrome, a rare disorder, Bajaj R, et al. (2005). Nonpolyalanine repeat mutations produce more severe disruptions of Phox2b function, such as HSCR and neural crest tumors, Berry-Kravis EM, et al. (2006), Neuroblastomas are biologically and clinically heterogeneous tumors. Approximately 10% of all childhood cancers are neuroblastomas (NB), tumors of the sympathetic (sympatho-adrenal lineage) nervous system, and hereditary predisposition to NB accounts for less than 5% of these neuroblastomas. Germline defects in Phox2b have been linked to a predisposition to hereditary NB, Trochet D, et al. (2004); Mosse YP, et al. (2004); Bourdeault F et al. (2005). Phox2b mutations may account for a specific phenotype of neuroblastoma, Perri P, et al. (2005). Sigma offers antibodies, shRNAs and other products useful for the study of the PHOX2B. References:
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