Disrupted Trigeminal Ganglion Development in a Mouse Model of Familial Dysautonomia

Abstract

Neurons in the trigeminal ganglion (TG) relay somatosensory information from the face and oral cavity to the central nervous system. Arising from the differentiation of both neural crest cell and ectodermal placode cell precursors during embryogenesis, neurons in the TG ultimately encode one sensory modality (i.e., touch, pain, temperature). TG neuron identity is discernable by particular molecular markers, including the mutually exclusive expression of the neurotrophin receptors TrkA, TrkB, or TrkC, which are required for long-term neuronal function and survival. While little is known about the mechanisms that establish and maintain distinct neuronal subpopulations in the TG, disease studies offer some insight. Familial Dysautonomia (FD) is a hereditary neuropathy caused by a mutation in Elongator complex protein 1 (ELP1), which leads to reduced ELP1 protein levels in sensory and autonomic neurons. FD patients have clinical deficits that point to abnormal TG function, including impaired sensation of facial pain and temperature. Moreover, FD patients have smaller trigeminal nerves compared to healthy controls, in the absence of overt degeneration. Given these findings, we hypothesize that ELP1 is necessary for the development and survival of TG sensory neurons. Our initial results uncovered cytoplasmic Elp1 expression in both placode cell- and neural crest cell-derived neurons of the developing mouse TG starting from embryonic day (E)10.5. Using a conditional knockout mouse model in which Elp1 is deleted from Wnt1-positive neural crest cells and derivatives, including sensory neurons, we next examined the effect of Elp1 loss on TG development. Our preliminary data reveal Elp1 depletion from neural crest cells leads to abnormal TG morphology and fewer trigeminal nerve branches as early as embryonic day (E)11, a phenotype that persists throughout development and suggests defects in both neural crest- and placode cell-derived neurons in the TG. TrkA-expressing neurons, which typically function in pain perception, are especially vulnerable to Elp1 loss during this period of TG formation. By E12.5, we observe decreased TrkA expression in distal trigeminal nerve endings and fewer TrkA-positive neuron cell bodies in the TG. Analyses from TUNEL staining reveal increased cell death in the TG at E12.5, suggesting TrkA-expressing neurons, progenitor cells, and/or supporting cells may undergo aberrant apoptosis in Elp1 conditional knockout TG. Together, our results confirm a role for Elp1 in the development and survival of TG sensory neurons. These findings help explain the loss of facial sensation in FD and may guide future therapeutic interventions to increase quality of life for FD patients.