Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of Familial Dysautonomia

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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.

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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.

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Carrie E Leonard

Department of Avian and Animal Sciences, University of Maryland, College Park, College Park, United States

Competing interests
No competing interests declared.
Jolie Quiros

Department of Avian and Animal Sciences, University of Maryland, College Park, College Park, United States

Competing interests
No competing interests declared.
Frances Lefcort

Department of Cell Biology and Neuroscience, Montana State University, Bozeman, United States

Competing interests
Frances Lefcort, is the Co-Chair of the Scientific Advisory Board of the Familial Dysautonomia Foundation, Inc..
Lisa A Taneyhill

Department of Avian and Animal Sciences, University of Maryland, College Park, College Park, United States

For correspondence
ltaney@umd.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-8630-2514

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).

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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.