Neural Crest-Specific Elp1 Deletion Disrupts Trigeminal Ganglion Development in a Model of Familial Dysautonomia

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R2520.

ABSTRACT

Neurons in the trigeminal ganglion relay sensory information from the face and oral cavity to the brain. The trigeminal ganglion is unique in its complexity, containing a mixed population of modality-specific (i.e., touch, pain) neurons derived from both neural crest and placodal precursors. The identity of trigeminal ganglion neurons is associated with the expression of Trk neurotrophin receptors, which are required for long-term neuronal function and survival. Within sensory ganglia, nociceptive neurons that detect pain or temperature generally express TrkA, while mechanoreceptors responding to touch express TrkB or TrkC. However, the processes that guide the emergence and maintenance of distinct neuronal subpopulations in the trigeminal ganglion are poorly understood. We recently uncovered a role for Elongator complex protein 1 (Elp1) in the maintenance of TrkA-expressing trigeminal ganglion nociceptors. Mutation of ELP1 causes Familial Dysautonomia (FD), a fatal neuropathy characterized, in part, by trigeminal sensory deficits, including impaired facial nociception. In a mouse model of FD, where Elp1 is deleted from neural crest derivatives (Elp1 CKO), we found that Elp1 is required for proper trigeminal nerve morphology. Moreover, loss of Elp1 reduces TrkA levels and enhances death of TrkA neurons during embryogenesis, explaining the facial sensory impairments experienced by FD patients. Given the targeted effects on TrkA neurons in Elp1 CKO, we hypothesized that most TrkA neurons in the trigeminal ganglion arise from the neural crest, while TrkB and TrkC neurons originate from placode cells. To address this, we first examined whether individual Trk receptors are co-expressed with the transcription factor Six1, which has previously been used to identify placodal neurons in the trigeminal ganglion. We discovered that Six1 is expressed in waves, marking newly differentiated trigeminal ganglion neurons regardless of presumptive placode or neural crest origin. Without bona fide immunohistochemical lineage markers, a Wnt1-Cre reporter mouse was used to identify neural crest (Wnt1-Cre recombined) versus placode (not recombined) derivatives. In support of our hypothesis, we observed a majority of TrkA neurons in the trigeminal ganglion had previously undergone Cre recombination, indicating trigeminal ganglion nociceptors are largely neural crest-derived. In contrast, most TrkB and TrkC neurons were not targeted for recombination, confirming trigeminal ganglion mechanoreceptors generally arise from placodes. Lastly, the majority of Six1-expressing cells were, indeed, Wnt1-Cre recombined once neural crest neuronal differentiation commenced in the trigeminal ganglion, confirming that Six1 is not exclusively expressed by placodal neurons at later stages. Future studies will expand upon this work by crossing the Wnt1-Cre reporter with Elp1 CKO to evaluate how Elp1 regulates the development and interactions of neural crest versus placodal derivatives within the trigeminal ganglion. Together, these findings provide novel insight into the origin and maintenance of trigeminal ganglion neurons and enhance our understanding of the pathogenesis of FD and other sensory nerve disorders.

PMID:35557309 | DOI:10.1096/fasebj.2022.36.S1.R2520