Phox2bcontrols the development of peripheral chemoreceptors and afferent visceral pathways

Abstract

We report that the afferent relays of visceral (cardiovascular, digestive and respiratory) reflexes, differentiate under the control of the paired-like homeobox gene Phox2b: the neural crest-derived carotid body, a chemosensor organ, degenerates in homozygous mutants, as do the three epibranchial placode-derived visceral sensory ganglia (geniculate, petrosal and nodose), while their central target, the nucleus of the solitary tract,which integrates all visceral information, never forms. These data establish Phox2b as an unusual `circuit-specific' transcription factor devoted to the formation of autonomic reflex pathways. We also show that Phox2b heterozygous mutants have an altered response to hypoxia and hypercapnia at birth and a decreased tyrosine hydroxylase expression in the petrosal chemosensory neurons, thus providing mechanistic insight into congenital central hypoventilation syndrome, which is associated with heterozygous mutations in PHOX2B.

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.…”

The homeoprotein Phox2b commands a somatic‐to‐visceral switch in cranial sensory pathways

“…In the hindbrain, relay sensory neurons of the nTS are born from E9.5 to E13.5 (10) in the domain of dA3 progenitors, which extends from rhombomere (r) 4 to r7 (11,12) and switch on Phox2b postmitotically (9). In homozygous Phox2b null embryos, nTS precursors switch on Lmx1b and Rnx/Tlx3 and start migrating ventrally (9)-as they do in heterozygous or wild-type embryos (9,12).…”

“…In homozygous Phox2b null embryos, nTS precursors switch on Lmx1b and Rnx/Tlx3 and start migrating ventrally (9)-as they do in heterozygous or wild-type embryos (9,12). However, at E12.5, most become undetectable using LacZ as a reporter (9).…”

“…In homozygous Phox2b null embryos, nTS precursors switch on Lmx1b and Rnx/Tlx3 and start migrating ventrally (9)-as they do in heterozygous or wild-type embryos (9,12). However, at E12.5, most become undetectable using LacZ as a reporter (9). At the end of gestation, a loss of tissue is detected where the nTS should be, but no sign of cell death precedes it, and some LacZ-positive cells are found misplaced in the ventrolateral medulla (9), hinting at a fate switch.…”

“…However, at E12.5, most become undetectable using LacZ as a reporter (9). At the end of gestation, a loss of tissue is detected where the nTS should be, but no sign of cell death precedes it, and some LacZ-positive cells are found misplaced in the ventrolateral medulla (9), hinting at a fate switch.…”