ArticleProceedings of the National Academy of Sciences of the United States of America2015
Giant ankyrin-G: a critical innovation in vertebrate evolution of fast and integrated neuronal signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers.
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Who cites it
114 citing papers in PubMed, 178 citations in OpenAlex.
- Surveying alternative transcripts of disease-associated genes and their cell type specificity - a case study with ANK3.Translational psychiatry · 2026Article
- Article
- A functional role for Septin-2 in the maintenance of the axon initial segment and in human cognitive development.Brain : a journal of neurology · 2026Article
- Subcortical Dendritic Scaffolding in Autism Spectrum Disorder: A Testable ANK2-SCN2A-SHANK Framework.International journal of molecular sciences · 2026Review
- Abl kinase activation promotes axon initial segment disassembly and protein sorting defects in Alzheimer's disease.BMC biology · 2026Article
- Axon Initial Segment: Structure, Biological Functions, Diseases, and Therapeutic Targets.MedComm · 2026Review
- A neuron type-specific microexon in Ank3/ankyrin-G modulates calcium activity and neuronal excitability.Nature communications · 2026Article
- Reframing the axon initial segment: Giant ankyrin-G as a modulator of excitability and plasticity in neurodevelopment.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Purkinje cell-specific loss of Neurofascin and Ankyrin G causes disruption of axon initial segments, neurodegeneration, and cerebellar ataxia.Frontiers in cellular neuroscience · 2026Article
- A neuron type-specific microexon inbioRxiv : the preprint server for biology · 2025Article
- Impaired AIS plasticity in ankyrin-G mutant mice alters cortical excitability and behavior.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cytoskeletal scaffolding of NaCurrent opinion in cell biology · 2025Review
- Regulation of neuronal ankyrin localization and function by post-translational modifications.Biochemical Society transactions · 2025Review
- Ankyrins are dispensable for mechanotransduction by cochlear hair cells.Hearing research · 2025Article
- Axon initial segment structure and function in health and disease.Physiological reviews · 2025Review
- Article
- Age-dependent regulation of axoglial interactions and behavior by oligodendrocyte AnkyrinG.Nature communications · 2024Article
- Alterations in the axon initial segment plasticity is involved in early pathogenesis in Alzheimer's disease.MedComm · 2024Article
- Specific and Plastic: Chandelier Cell-to-Axon Initial Segment Connections in Shaping Functional Cortical Network.Neuroscience bulletin · 2024Review
- TRIM46 Is Required for Microtubule Fasciculation In Vivo But Not Axon Specification or Axon Initial Segment Formation.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
54 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Axon initial segments (AISs) and nodes of Ranvier are sites of clustering of voltage-gated sodium channels (VGSCs) in nervous systems of jawed vertebrates that facilitate fast long-distance electrical signaling. We demonstrate that proximal axonal polarity as well as assembly of the AIS and normal morphogenesis of nodes of Ranvier all require a heretofore uncharacterized alternatively spliced giant exon of ankyrin-G (AnkG). This exon has sequence similarity to I-connectin/Titin and was acquired after the first round of whole-genome duplication by the ancestral ANK2/ANK3 gene in early vertebrates before development of myelin. The giant exon resulted in a new nervous system-specific 480-kDa polypeptide combining previously known features of ANK repeats and β-spectrin-binding activity with a fibrous domain nearly 150 nm in length. We elucidate previously undescribed functions for giant AnkG, including recruitment of β4 spectrin to the AIS that likely is regulated by phosphorylation, and demonstrate that 480-kDa AnkG is a major component of the AIS membrane "undercoat' imaged by platinum replica electron microscopy. Surprisingly, giant AnkG-knockout neurons completely lacking known AIS components still retain distal axonal polarity and generate action potentials (APs), although with abnormal frequency. Giant AnkG-deficient mice live to weaning and provide a rationale for survival of humans with severe cognitive dysfunction bearing a truncating mutation in the giant exon. The giant exon of AnkG is required for assembly of the AIS and nodes of Ranvier and was a transformative innovation in evolution of the vertebrate nervous system that now is a potential target in neurodevelopmental disorders.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.