Ribosomal profiling of the geniculate ganglion identifies the receptor ALK as critical for the development and maintenance of oral sensory neurons

The geniculate ganglion (GG) consists of two populations of neurons, sensory neurons that innervate the oral cavity and express the transcription factor <i>Phox2b</i>, and somatosensory neurons that innervate the pinna and express <i>Brn3a</i> To identify signaling pathways necessary for oral sensory neuron development and physiology, the translatome of <i>Phox2b+</i> 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. <i>In situ</i> hybridization revealed that <i>Alk</i> was expressed in nearly all <i>Phox2b</i>+ neurons and was absent from <i>Phox2b</i>- neurons. <i>Alk</i> was robustly expressed in the GG at all ages examined, from E14.5 into adulthood. To determine whether <i>Alk</i> is necessary for development of the peripheral gustatory system, GG and taste buds (TBs) from postnatal day 3 (P3), P14 and P30 <i>Alk</i> ^-/- and <i>Alk</i> ^+/+ male and female mice were examined. Neither oral sensory neurons (PHOX2B+) nor total GG neurons (TUJ1+) were lost in <i>Alk</i> ^-/- mice. However, TB number, volume and innervation were all significantly decreased in <i>Alk</i> ^-/- mice, as compared to <i>Alk</i> ^+/+ mice. <i>ALK</i> mutations cause a portion of non-small cell lung cancers, and treatment with selective ALK inhibitors, such as Ceritinib, frequently causes dysgeusia. Male and female mice receiving Ceritinib for 30 days showed a dramatic reduction in TB volume and TB innervation, as compared to 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 life-long maintenance of oral sensory neurons.<b>Significance Statement</b> The geniculate ganglion consists of two neuronal populations, oral sensory neurons that express the transcription factor <i>Phox2b</i>, and somatosensory neurons that innervate the pinna and express <i>Brn3a</i> Translatomics of <i>Phox2b</i>+ neurons identified they receptor tyrosine kinase ALK as enriched in these neurons. While there was no loss of Phox2b+ neurons in <i>Alk</i> knockout mice, there were target abnormalities including a reduction in taste bud number and volume, along with diminished taste bud innervation. Treatment of cancer patients with selective ALK inhibitors, such as Ceritinib, causes dysgeusia. Mice receiving Ceritinib had a dramatic reduction in taste bud volume and innervation, and a significant portion of PHOX2B+ neurons died, demonstrating that ALK is critical for development and maintenance of oral sensory neurons.