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

Leonard, Carrie L.; Quiros, Jolie; Lefcort, Frances; Taneyhill, Lisa A.

doi:10.7554/elife.71455

Cited by 12 publications

(10 citation statements)

References 96 publications

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“…Interestingly, we observed that the majority of TUNEL signal was found adjacent to Sox10-positive nuclei, which may be identifying future glial cells. This phenomenon, seen previously 61,62 suggests that glial cells aid in the removal of debris during gangliogenesis. When looking at general trends of cell death occurring within the trigeminal ganglion over development, the first time point had decreased apoptosis compared to the other two time points.…”

Section: Morphological Changes After N-cadherin Knockdown From Placod...supporting

confidence: 67%

N-cadherin facilitates trigeminal sensory neuron outgrowth and target tissue innervation

Halmi,

McIntosh,

Leonard

et al. 2024

Preprint

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During the development of the sensory nervous system, various cell types converge to form different tissues. The trigeminal ganglion houses the cell bodies for the trigeminal nerve and exemplifies these intercellular interactions, as it is formed from the condensation of two diverse precursor cell populations, neural crest cells and placode cells. The dual origin of the trigeminal ganglion has been understood for decades, but the molecules that orchestrate this process remain relatively unknown. Assembling the trigeminal ganglion is mediated by cell adhesion molecules including the protein neural cadherin (N-cadherin), expressed first in placode-derived neurons and later in all trigeminal sensory neurons. Prior studies have shown that N-cadherin knockdown in chick trigeminal placode cells leads to early defects in trigeminal ganglion assembly by impacting the ability of placode-derived neurons to properly condense with undifferentiated neural crest cells. Later functions for N-cadherin in chick trigeminal gangliogenesis, however, are unknown. Using morpholino-mediated knockdown of N-cadherin in chick trigeminal placode cells, we examined trigeminal ganglion development at later developmental stages, when neural crest cells are differentiating into neurons. Through these experiments, we uncovered a sustained negative impact on the trigeminal ganglion, leading to decreases in ganglion size, nerve outgrowth, and branching to target tissuesin vivo. Further, blocking the adhesive function of N-cadherin reveals its importance in the outgrowth ability for some, but not all, trigeminal neuronsin vitro. These deficits reflect potential cell and non-cell autonomous effects on placodal and neural crest-derived neurons, respectively, and point to the importance of N-cadherin-mediated adhesion among trigeminal sensory neurons. Our findings reveal continued adhesion-dependent functions for N-cadherin in the trigeminal ganglion, which will aid in the understanding of its tissue-specific roles.

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Section: Morphological Changes After N-cadherin Knockdown From Placod...supporting

confidence: 67%

N-cadherin facilitates trigeminal sensory neuron outgrowth and target tissue innervation

Halmi,

McIntosh,

Leonard

et al. 2024

Preprint

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“…In this study, Elp1 was critical for cell survival of spinal motor neurons and cortical neurons (Chaverra et al 2017). Similarly, knockout of Elp1 in neural crest-derived neurons resulted in increased neuronal cell death of selective populations and in diminished nerve growth as development proceeded (George et al 2013; Jackson et al 2014; Leonard et al 2022). Overall, combining these published studies with our current work confirms the essentiality of Elp1 in maintaining neuronal survival as a key function in maintaining brain health.…”

Section: Discussionmentioning

confidence: 99%

Loss of the Familial Dysautonomia geneElp1in cerebellar granule cell progenitors leads to ataxia in mice

Manz,

da Silva,

Schouw

et al. 2024

Preprint

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Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have been described. ELP1 is highly expressed in the normal developing and adult cerebellum, but its role in cerebellum development is unknown. To investigate the cerebellar function of Elp1, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent 7 days after birth, when Elp1cKO animals also exhibited fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 within the developing cerebellum, and suggests that Elp1 loss in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Harripaul,

Morini,

Salani

et al. 2023

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Familial dysautonomia (FD) is a rare recessive neurodevelopmental disease caused by a splice mutation in the Elongator acetyltransferase complex subunit 1 (ELP1) gene. This mutation results in a tissue-specific reduction of ELP1 protein, with the lowest levels in the central and peripheral nervous systems (CNS and PNS, respectively). FD patients exhibit complex neurological phenotypes due to the loss of sensory and autonomic neurons. Disease symptoms include decreased pain and temperature perception, impaired or absent myotatic reflexes, proprioceptive ataxia, and progressive retinal degeneration. While the involvement of the PNS in FD pathogenesis has been clearly recognized, the underlying mechanisms responsible for the preferential neuronal loss remain unknown. In this study, we aimed to elucidate the molecular mechanisms underlying FD by conducting a comprehensive transcriptome analysis of neuronal tissues from the phenotypic mouse model TgFD9; Elp1Δ20/flox. This mouse recapitulates the same tissue-specific ELP1 mis-splicing observed in patients while modeling many of the disease manifestations. Comparison of FD and control transcriptomes from dorsal root ganglion (DRG), trigeminal ganglion (TG), medulla (MED), cortex, and spinal cord (SC) showed significantly more differentially expressed genes (DEGs) in the PNS than the CNS. We then identified genes that were tightly co-expressed and functionally dependent on the level of full-length ELP1 transcript. These genes, defined as ELP1 dose-responsive genes, were combined with the DEGs to generate tissue-specific dysregulated FD signature genes and networks. Within the PNS networks, we observed direct connections between Elp1 and genes involved in tRNA synthesis and genes related to amine metabolism and synaptic signaling. Importantly, transcriptomic dysregulation in PNS tissues exhibited enrichment for neuronal subtype markers associated with peptidergic nociceptors and myelinated sensory neurons, which are known to be affected in FD. In summary, this study has identified critical tissue-specific gene networks underlying the etiology of FD and provides new insights into the molecular basis of the disease.

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

Cited by 12 publications

References 96 publications

N-cadherin facilitates trigeminal sensory neuron outgrowth and target tissue innervation

N-cadherin facilitates trigeminal sensory neuron outgrowth and target tissue innervation

Loss of the Familial Dysautonomia geneElp1in cerebellar granule cell progenitors leads to ataxia in mice

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

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