Homeoprotein Phox2b commands a somatic-to-visceral switch in cranial sensory pathways

Abstract

Taste and most sensory inputs required for the feedback regulation of digestive, respiratory, and cardiovascular organs are conveyed to the central nervous system by so-called "visceral" sensory neurons located in three cranial ganglia (geniculate, petrosal, and nodose) and integrated in the hindbrain by relay sensory neurons located in the nucleus of the solitary tract. Visceral sensory ganglia and the nucleus of the solitary tract all depend for their formation on the pan-visceral homeodomain transcription factor Phox2b, also required in efferent neurons to the viscera. We show here, by genetically tracing Phox2b + cells, that in the absence of the protein, many visceral sensory neurons (first-and second-order) survive. However, they adopt a fate-including molecular signature, cell positions, and axonal projections-akin to that of somatic sensory neurons (first-and second-order), located in the trigeminal, superior, and jugular ganglia and the trigeminal sensory nuclei, that convey touch and pain sensation from the orofacial region. Thus, the cranial sensory pathways, somatic and visceral, are related, and Phox2b serves as a developmental switch from the former to the latter.

Several Cis-regulatory Elements Control mRNA Stability, Translation Efficiency, and Expression Pattern of Prrxl1 (Paired Related Homeobox Protein-like 1)

“…This increase in Prrxl1 expression was suggested to be mediated by the increase of Brn3a, which, in turn, is directly repressed by Phox2b (7). On the contrary, Prrxl1 expression in the nuclear TS progenitor domains of the hindbrain is not affected by Phox2b inactivation, suggesting that the repression of Prrxl1 by Phox2b only occurs in the visceral sensory ganglia (7). In accordance, Phox2b is not required for drgx expression in the zebrafish hindbrain.…”

“…Among the tested candidates, Tlx3, Brn3a, and Phox2b induced Prrxl1 promoter activity, but only Phox2b was able to bind to this HD motif. Co-expression of Phox2b and Prrxl1 or its zebrafish ortologue, drgx, was only detected in the visceral sensory pathway, namely in the facial, glossopharyngeal, and vagal cranial ganglia and their target relay neurons in the hindbrain (6,7,63).We, therefore, presume that the P3 activity observed in the transgenic line (Fig. 6) may be controlled, at least to some extent, by Phox2b.…”

“…Nonetheless, in the mouse, visceral sensory neurons switch to a somatic fate in the absence of Phox2b acquiring a molecular profile similar to that of somatic sensory neurons at later developmental stages, with higher expression of Prrxl1 and Brn3a (7). This increase in Prrxl1 expression was suggested to be mediated by the increase of Brn3a, which, in turn, is directly repressed by Phox2b (7).…”

“…Prrxl1 has emerged as a crucial molecule in the development of the pain-perception circuitry, especially in the establishment of the nociceptive DRG-spinal pathway. Prrxl1 is also expressed in sensory cranial ganglia and their target relay neurons in the hindbrain (6,7). Nevertheless, the role of Prrxl1 in these tissues is poorly studied.…”

Paired related homeobox protein‐like 1 (Prrxl1) controls its own expression by a transcriptional autorepression mechanism

“…To date, Phox2b HD transcription factor, which is transiently coexpressed with Prrxl1 at early development (from E10.5 to 13.5) of facial-glossopharyngeal and vagal ganglia [6,23], is the only known direct regulator of Prrxl1 transcription. Both Prrxl1 and Phox2 bind to the minimal TATA box promoter region of Prrxl1, but have opposing transcriptional activities [24] and (Fig.…”