Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of Familial Dysautonomia
Abstract
Familial Dysautonomia (FD) is a sensory and autonomic neuropathy caused by mutations in Elongator complex protein 1 (ELP1). FD patients have small trigeminal nerves and impaired facial pain and temperature perception. These signals are relayed by nociceptive neurons in the trigeminal ganglion, a structure comprised of both neural crest- and placode-derived cells. Mice lacking Elp1 in neural crest derivatives ('Elp1 CKO') are born with small trigeminal ganglia, suggesting Elp1 is important for trigeminal ganglion development, yet the function of Elp1 in this context is unknown. We demonstrate that Elp1, expressed in both neural crest- and placode-derived neurons, is not required for initial trigeminal ganglion formation. However, Elp1 CKO trigeminal neurons exhibit abnormal axon outgrowth and deficient target innervation. Developing nociceptors expressing the receptor TrkA undergo early apoptosis in Elp1 CKO, while TrkB- and TrkC-expressing neurons are spared, indicating Elp1 supports the target innervation and survival of trigeminal nociceptors. Further, we demonstrate that specific TrkA deficits in the Elp1 CKO trigeminal ganglion reflect the neural crest lineage of most TrkA neurons, versus the placodal lineage of most TrkB and TrkC neurons. Altogether, these findings explain defects in cranial gangliogenesis that may lead to loss of facial pain and temperature sensation in FD.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source Data files have been provided for Figures 2-9.
Article and author information
Author details
Funding
National Institutes of Health
- Lisa A Taneyhill
National Institutes of Health
- Frances Lefcort
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal care and use described herein was in accordance with federal and institutional guidelines and approved by Montana State University's and University of Maryland's IACUC, under protocols #2018-81 (MSU) and #R-MAR-20-15 (UMD).
Reviewing Editor
- Marianne E Bronner, California Institute of Technology, United States
Publication history
- Received: June 19, 2021
- Accepted: June 17, 2022
- Accepted Manuscript published: June 17, 2022 (version 1)
- Accepted Manuscript updated: June 22, 2022 (version 2)
Copyright
© 2022, Leonard et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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