Elp1 is required for development of visceral sensory peripheral and central circuitry

Abstract

Cardiovascular instability and a blunted respiratory drive in hypoxic conditions, are hallmark features of the genetic sensory and autonomic neuropathy, familial dysautonomia (FD). FD results from a mutation in the gene ELP1, whose encoded protein is a scaffolding subunit of the six subunit Elongator complex. In mice, we and others have shown that Elp1 is essential for the normal development of neural crest derived-dorsal root ganglia (DRG) sensory neurons. Whether Elp1 is also required for development of ectodermal placode-derived visceral sensory receptors which are required for normal baroreception and chemosensory responses, has not been investigated. Using mouse models for FD, our data indicate that in fact the entire circuitry underlying baroreception and chemoreception is impaired due to a requirement for Elp1 not only in the visceral sensory neuron ganglia, but also for normal peripheral target innervation, and in their CNS synaptic partners in the medulla. Thus Elp1 is required in both placode- and neural crest-derived sensory neurons and its reduction aborts the normal development of neuronal circuitry essential for autonomic homeostasis and interoception.

Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of familial dysautonomia

“…Moreover, we did not detect similar neurodevelopmental perturbations in the exclusively placode-derived geniculate ganglion, which contains few, if any, TrkA-expressing neurons at E12.5. Given that Elp1 is expressed in placode-derived neurons ( Figure 1 and Figure 5—figure supplement 2 ), and recent reports showing Elp1 is required for the survival of TrkB-positive neurons in epibranchial ganglia ( Tolman et al, 2022 ), we suspect a placode-targeted deletion of Elp1 would lead to TrkB neuronal deficits in the trigeminal and geniculate ganglia. It is also possible that placode-derived TrkB or TrkC neurons will be indirectly affected at later timepoints in Elp1 CKO, given the important reciprocal interactions between the two lineages during trigeminal ganglion development ( Shiau et al, 2008 ; Shiau and Bronner-Fraser, 2009 ; Wu and Taneyhill, 2019 ; Steventon et al, 2014 ; Wu et al, 2014 ).…”

“…transcription) functions ( Dalwadi and Yip, 2018 ; Dietrich and Dragatsis, 2016 ; Lefcort et al, 2017 ). To date, animal studies emphasize defects in dorsal root, sympathetic, and enteric ganglia, which relay sensory and autonomic information from the trunk, limbs, and viscera to the CNS ( Abashidze et al, 2014 ; Cheng et al, 2015 ; George et al, 2013 ; Goffena et al, 2018 ; Hunnicutt et al, 2012 ; Jackson et al, 2014 ; Li et al, 2020 ; Morini et al, 2021 ; Tolman et al, 2022 ). However, there is a dearth of knowledge about Elp1 in the cranial ganglia, even when clinical deficits strongly implicate cranial sensory dysfunction in FD ( Mendoza-Santiesteban et al, 2017 ; Barlow, 2009 ; Geltzer et al, 1964 ; Gutiérrez et al, 2015 ; Palma et al, 2018 ; Won et al, 2019 ).…”

“…In dorsal root, epibranchial (sensory), and sympathetic (autonomic) ganglia, Elp1 is required for the generation and/or survival of TrkA and TrkB neurons, while TrkC neurons are spared during development ( George et al, 2013 ; Jackson et al, 2014 ; Tolman et al, 2022 ). In these contexts, neuronal loss has been attributed to decreased neurogenesis resulting from early differentiation and apoptosis of progenitors ( George et al, 2013 ; Goffena et al, 2018 ) and to severe target innervation defects and neuronal apoptosis due to insufficient neurotrophic support ( Jackson et al, 2014 ; Li et al, 2020 ; Tolman et al, 2022 ). Notably, other less common forms of HSANs arise from germline mutations in the genes encoding either TrkA or its high-affinity ligand, nerve growth factor (NGF; Schwartzlow and Kazamel, 2019 ).…”

Transcriptome analysis in a humanized mouse model of familial dysautonomia reveals tissue-specific gene expression disruption in the peripheral nervous system

“…FD is a progressive neurodegenerative disease that manifests in various debilitating symptoms including diminished pain and temperature perception, decreased or absent myotatic reflexes, proprioceptive ataxia, and retinal degeneration. Recent studies have provided compelling evidence linking the reduction of Elp1 to sensory neuronal loss and diminished tissue innervation (70)(71)(72). However, the intricate molecular mechanisms connecting ELP1 reduction with the phenotypic manifestations of the disease remain largely unknown.…”

First person – Zariah Tolman

“… ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Zariah Tolman is first author on ‘ Elp1 is required for development of visceral sensory peripheral and central circuitry ’, published in DMM. Zariah conducted the research described in this article while an undergraduate research assistant in Frances Lefcort's lab at Montana State University, Bozeman, MT, USA.…”