The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives

Abstract

The sympathetic, parasympathetic and enteric ganglia are the main components of the peripheral autonomic nervous system, and are all derived from the neural crest. The factors needed for these structures to develop include the transcription factor Mash1, the glial-derived neurotrophic factor GNDF and its receptor subunits, and the neuregulin signalling system, each of which is essential for the differentiation and survival of subsets of autonomic neurons. Here we show that all autonomic ganglia fail to form properly and degenerate in mice lacking the homeodomain transcription factor Phox2b, as do the three cranial sensory ganglia that are part of the autonomic reflex circuits. 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. Mutant ganglionic anlagen also fail to switch on the genes that encode two enzymes needed for the biosynthesis of the neurotransmitter noradrenaline, dopamine-beta-hydroxylase and tyrosine hydroxylase, demonstrating that Phox2b regulates the noradrenergic phenotype in vertebrates.

Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death

“…6 In PHOX2B-knockout mice the carotid body and autonomic visceral sensory ganglia, including the geniculate, petrosal, and nodose ganglia, fail to form properly and degenerate, and the solitary tract nucleus, their central target which integrates all visceral information including cardiorespiratory regulation, never develops. 25,26 This lack of visceral input may help explain the distinctive lack of flexibility of the cardiovascular system in children with CCHS, thereby increasing their vulnerability to sudden death. These knockout studies demonstrate the importance of PHOX2B in the development of the ANS, and suggest a mechanism by which a PHOX2B mutation might manifest as dysregulation of cardiac and respiratory rate and rhythm.…”

Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome

“…So far, only lowpenetrant predisposing mutations of the RET-Glial cell line-derived neurotrophic factor (GDNF), endothelin 3 (EDN3) and brain-derived neurotrophic factor (BDNF) pathways have been reported in a few individuals with CCHS [5][6][7] . Considering the broad range of defects in the ANS in CCHS on the one hand and the key role of Phox2b in the ontogeny of the ANS reflex circuits in mice 8,9 on the other hand, we regarded PHOX2B (also called PMX2B and NBPHOX) as a candidate gene in the disease.…”

Trim11 increases expression of dopamine β-hydroxylase gene by interacting with Phox2b

“…Phox2b is critical for the development of NA neuron both in the PNS and CNS [12,13]. We addressed whether Trim11 cooperates with Phox2b to transactivate NA neuron specific promoters.…”

“…cDNA was made from five μg of total RNA using superscript II (Invitrogen) with oligo (dT) [12][13][14][15][16][17][18] as a primer. For quantitative analysis of the expression level of mRNAs, real-time PCR analyses using SYBR green I were performed using DNA engine Opticon™ (MJ Research).…”

“…In contrast, Phox2b knockout mice showed developmental defects in all NA neurons of the CNS and PNS. Phox2b is required for brachial and visceral motoneurons in CNS and autonomic neurons (sympathetic, parasympathetic, and enteric) in PNS development [12,13], while Phox2a is required for cranial Oculomotor and Trochlear motor neurons [11]. In addition, reciprocal gene replacements in mice showed that Phox2a and Phox2b are not functionally equivalent [14].…”