Ribosomal Profiling of the Geniculate Ganglion Identifies the Receptor ALK as Critical for the Development and Maintenance of Oral Sensory Neurons

Abstract

The geniculate ganglion (GG) consists of two populations of neurons, sensory neurons that innervate the oral cavity and express the transcription factor Phox2b and somatosensory neurons that innervate the pinna and express Brn3a . To identify signaling pathways necessary for oral sensory neuron development and physiology, the translatome of Phox2b + GG neurons was selectively profiled using the RiboTag method. From this analysis, anaplastic lymphoma kinase (ALK) was identified as one of the most highly enriched tyrosine kinase receptors. In situ hybridization revealed that Alk was expressed in nearly all Phox2b + neurons and was absent from Phox2b − neurons. Alk was robustly expressed in GG at all ages examined, from Embryonic Day 14.5 into adulthood. To determine whether Alk is necessary for development of the peripheral gustatory system, GG and taste buds (TBs) from Postnatal Day 3 (P3), P14, and P30 Alk −/− and Alk +/+ male and female mice were examined. Neither oral sensory neurons (PHOX2B + ) nor total GG neurons (TUJ1 + ) died in Alk −/− mice. However, TB number, volume, and innervation were all significantly decreased in Alk −/− mice, as compared with Alk +/+ mice. ALK mutations cause a portion of nonsmall cell lung cancers, and treatment with ALK inhibitors, such as ceritinib, frequently causes dysgeusia. Mice receiving ceritinib for 30 d showed a dramatic reduction in TB volume and innervation, as compared with vehicle-treated controls. Somal diameters of oral sensory neurons atrophied and a significant portion of PHOX2B + neurons died in ceritinib-treated mice. ALK is thus critical for development and maintenance of oral sensory neurons.