title: Giant ankyrin-G: a critical innovation in vertebrate evolution of fast and integrated neuronal signaling.
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.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Jenkins
authors.affiliation: Department of Psychology and Neuroscience.
authors.forename: Namsoo
authors.initials: N
authors.lastname: Kim
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Jones
authors.affiliation: Department of Pharmacology and Cancer Biology.
authors.forename: Wei Chou
authors.initials: WC
authors.lastname: Tseng
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Tatyana M
authors.initials: TM
authors.lastname: Svitkina
authors.affiliation: Department of Psychology and Neuroscience.
authors.forename: Henry H
authors.initials: HH
authors.lastname: Yin
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Departments of Cell Biology and Neurobiology, Duke University Medical Center, Durham, NC 27710; and vann.bennett@duke.edu.
authors.forename: Vann
authors.initials: V
authors.lastname: Bennett
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism; D001369:Axons / Q000378:metabolism*; D019143:Evolution, Molecular; D005091:Exons; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D017434:Protein Structure, Tertiary; D011901:Ranvier's Nodes / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: C498995:Ank2 protein, mouse; C432674:Ank2 protein, rat; C094681:Ank3 protein, mouse; C490614:Ank3 protein, rat; D017487:Ankyrins
keywords: ankyrin-G; axon initial segment; axonal polarity; cognitive impairment disorder; neuropsychiatric disease