Transgenic Models Reveal Distinct Origins of Trk-expressing Neuronal Subpopulations in the Murine Trigeminal Ganglion

Abstract Body : Trigeminal ganglion neurons relay sensory information from diverse craniofacial regions to the central nervous system. The trigeminal ganglion uniquely contains intermingled neurons derived from neural crest and placode cells, whereas the two neuronal lineages are spatially distinct in other cranial ganglia. Trigeminal neuron identity is associated with the mutually exclusive expression of Trk neurotrophin receptors. Within sensory ganglia, neurons that detect pain or temperature (nociceptors) generally express TrkA, while touch-sensing and proprioceptive neurons (mechanoreceptors) express TrkB or TrkC. Yet mechanisms that guide the emergence and maintenance of distinct neuronal subpopulations in the trigeminal ganglion are poorly understood. We recently demonstrated that Elongator complex protein 1 (Elp1) is required for cranial sensory neuron development, and that loss of Elp1 from neural crest derivatives disrupts the growth and survival of TrkA-expressing trigeminal ganglion neurons. Given the targeted effects on nociceptors in a neural crest-specific knockout, we hypothesized that trigeminal ganglion nociceptors are neural crest-derived. To test this, Six1 expression was evaluated by immunohistochemistry, which has historically identified trigeminal placode-derived neurons. However, we discovered that Six1 is transiently expressed in all newly differentiated trigeminal ganglion neurons, regardless of cellular origin. Using a Wnt1-Cre reporter mouse, we determined that nearly all Six1-expressing cells during the height of neuronal differentiation in the trigeminal ganglion are neural crest-derived. Moreover, Six1 expression was restricted to TrkA neurons during the same developmental window. Finally, we found that a majority of TrkA neurons had previously undergone Wnt1-Cre recombination, while most TrkB and TrkC neurons had not. These results indicate a large proportion of nociceptors in the mouse trigeminal ganglion are neural crest-derived, while mechanoreceptors generally arise from placode cells. Using genome-integrating fluorescent reporters in chick and mouse, future studies will characterize the developmental trajectories of neural crest- versus placode-derived trigeminal ganglion neurons in order to evaluate whether the fate and function of neuronal subpopulations, based on cellular origin, is conserved. Together, these findings provide novel insight into the origin and maintenance of trigeminal ganglion neurons and shed light on the etiology of developmental sensory neuropathies. This work was supported by NIH R01DE024217 (LAT) and AAA Postdoctoral Fellowship (CEL).