ArticleThe Journal of clinical investigation2020
Retrograde nerve growth factor signaling abnormalities in familial dysautonomia.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 21 citations in OpenAlex.
- Review of published research on primary dysautonomia of domestic animals.The Veterinary record · 2026Review
- Elp1 function in placode-derived neurons is critical for proper trigeminal ganglion development.Developmental dynamics : an official publication of the American Association of Anatomists · 2025Article
- Article
- Hormonal Imbalance as a Prognostic Factor of Physical Development of Children with Intellectual Disability.Children (Basel, Switzerland) · 2024Article
- The Alteration of Proteomic Profiles in Hippocampus of Type 2 Diabetic Mice Associated With Cognitive Impairment.Bioinformatics and biology insights · 2024Article
- Norepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models.Nature communications · 2022Article
- Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of familial dysautonomia.eLife · 2022Article
- Elp1 is required for development of visceral sensory peripheral and central circuitry.Disease models & mechanisms · 2022Article
- Elp1 facilitates RAD51-mediated homologous recombination repair via translational regulation.Journal of biomedical science · 2021Article
- The sympathetic nervous system in development and disease.Nature reviews. Neuroscience · 2021Review
- Retrograde nerve growth factor signaling abnormalities and the pathogenesis of familial dysautonomia.Neural regeneration research · 2021Article
- (H)Elping nerve growth factor: Elp1 inhibits TrkA's phosphatase to maintain retrograde signaling.The Journal of clinical investigation · 2020Article
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3 authors at 1 institution in 1 country.
Funding
Abstract
Familial dysautonomia (FD) is the most prevalent form of hereditary sensory and autonomic neuropathy (HSAN). In FD, a germline mutation in the Elp1 gene leads to Elp1 protein decrease that causes sympathetic neuron death and sympathetic nervous system dysfunction (dysautonomia). Elp1 is best known as a scaffolding protein within the nuclear hetero-hexameric transcriptional Elongator protein complex, but how it functions in sympathetic neuron survival is very poorly understood. Here, we identified a cytoplasmic function for Elp1 in sympathetic neurons that was essential for retrograde nerve growth factor (NGF) signaling and neuron target tissue innervation and survival. Elp1 was found to bind to internalized TrkA receptors in an NGF-dependent manner, where it was essential for maintaining TrkA receptor phosphorylation (activation) by regulating PTPN6 (Shp1) phosphatase activity within the signaling complex. In the absence of Elp1, Shp1 was hyperactivated, leading to premature TrkA receptor dephosphorylation, which resulted in retrograde signaling failure and neuron death. Inhibiting Shp1 phosphatase activity in the absence of Elp1 rescued NGF-dependent retrograde signaling, and in an animal model of FD it rescued abnormal sympathetic target tissue innervation. These results suggest that regulation of retrograde NGF signaling in sympathetic neurons by Elp1 may explain sympathetic neuron loss and physiologic dysautonomia in patients with FD.
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