Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage

Morini, Elisabetta; Gao, Dadi; Logan, Emily; Salani, Monica; Krauson, Aram J.; Chekuri, Anil; Chen, Yei Tsung; Ragavendran, Ashok; Chakravarty, Probir; Erdin, Serkan; Stortchevoi, Alexei; Svejstrup, Jesper Q.; Talkowski, Michael E.; Slaugenhaupt, Susan

doi:10.1016/j.jgg.2021.11.011

Cited by 6 publications

(9 citation statements)

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“…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 ).…”

Section: Discussionmentioning

confidence: 99%

“…For example, Elp1 may be required for axonal outgrowth via alternative, NGF-independent mechanisms, including anterograde trafficking of receptors for critical growth factors or guidance molecules and/or regulation of local protein synthesis, all of which are required for growing axons ( Scott-Solomon and Kuruvilla, 2018 ; Ascano et al, 2009 ; Cioni et al, 2019 ; Korsak et al, 2016 ; Batista and Hengst, 2016 ; Kang and Schuman, 1996 ). Recently, Elp1 has been shown to regulate neuronal gene expression in a dose-dependent manner in a humanized mouse model of FD ( Morini et al, 2021 ). Importantly, these functions of Elp1 could be direct or indirect via its essential role as part of the elongator complex in modifying tRNAs during translation ( Cameron et al, 2021 ; Chen et al, 2009b ; Chen et al, 2009a ; Goffena et al, 2018 ; Huang et al, 2005 ; Huang et al, 2008 ; Karlsborn et al, 2014 ; Karlsborn et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

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

Leonard

Quiros

Lefcort

et al. 2022

eLife

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Leonard

Quiros

Lefcort

et al. 2022

eLife

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“…Moreover, the fact that mutations and/or variants in ELP2-4 , are associated with distinct neurological disorders (albeit with some overlapping features) ranging from intellectual disability to ALS but excluding the sympathetic, sensory, and optic neuropathies exhibited by FD patients, may speak to variation in function of the Elp subunits independent of their joint actions as part of the elongator complex. Although the vast majority of Elp1 is localized to the cytoplasm, there are reports that the elongator complex is also involved in transcriptional elongation (Otero et al 1999; Hawkes et al 2002; Close et al 2006; Morini et al 2021); this effect may be the indirect consequence of changes in the cells’ proteome that occur with loss of elongator function.…”

Section: Discussionmentioning

confidence: 99%

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

Lefcort

Chaverra

Tolman

et al. 2022

Preprint

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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.

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“…Moreover, the fact that mutations and/or variants in ELP2-ELP4 , are associated with distinct neurological disorders (albeit with some overlapping features), ranging from intellectual disability to amyotrophic lateral sclerosis, but excluding the sympathetic, sensory and optic neuropathies exhibited by FD patients, may indicate variation in function of the Elp subunits independent of their joint actions as part of the Elongator complex. Although the vast majority of Elp1 is localized to the cytoplasm, there are reports that the Elongator complex is also involved in transcriptional elongation ( Otero et al, 1999 ; Hawkes et al, 2002 ; Close et al, 2006 ; Morini et al, 2021 ); this effect may be the indirect consequence of changes in the cells' proteome that occur with loss of Elongator function.…”

Section: Discussionmentioning

confidence: 99%

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

Tolman

Chaverra

George

et al. 2022

Disease Models &Amp; Mechanisms

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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, the encoded protein of which 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 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, we here show that the entire circuitry underlying baroreception and chemoreception is impaired due to a requirement for Elp1 in the visceral sensory neuron ganglia, as well as for normal peripheral target innervation, and in their central nervous system 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. This article has an associated First Person interview with the first author of the paper.

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Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage

Cited by 6 publications

References 86 publications

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

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

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

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

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