ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity

Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):15262-15271. doi: 10.1073/pnas.1904348116. Epub 2019 Jul 8.

Abstract

Giant ankyrin-B (ankB) is a neurospecific alternatively spliced variant of ANK2, a high-confidence autism spectrum disorder (ASD) gene. We report that a mouse model for human ASD mutation of giant ankB exhibits increased axonal branching in cultured neurons with ectopic CNS axon connectivity, as well as with a transient increase in excitatory synapses during postnatal development. We elucidate a mechanism normally limiting axon branching, whereby giant ankB localizes to periodic axonal plasma membrane domains through L1 cell-adhesion molecule protein, where it couples microtubules to the plasma membrane and prevents microtubule entry into nascent axon branches. Giant ankB mutation or deficiency results in a dominantly inherited impairment in selected communicative and social behaviors combined with superior executive function. Thus, gain of axon branching due to giant ankB-deficiency/mutation is a candidate cellular mechanism to explain aberrant structural connectivity and penetrant behavioral consequences in mice as well as humans bearing ASD-related ANK2 mutations.

Keywords: ANK2; L1CAM; axon branching; giant ankyrin-B; nonsyndromic autism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Ankyrins / genetics*
  • Ankyrins / metabolism
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / metabolism
  • Autism Spectrum Disorder / physiopathology
  • Behavior, Animal
  • Cell Membrane / metabolism
  • Cell Membrane / ultrastructure
  • Connectome
  • Disease Models, Animal
  • Executive Function / physiology
  • Gene Expression
  • Gene Knock-In Techniques
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Microtubules / metabolism
  • Microtubules / ultrastructure
  • Mutation
  • Neural Cell Adhesion Molecule L1 / genetics*
  • Neural Cell Adhesion Molecule L1 / metabolism
  • Neuronal Outgrowth*
  • Neurons / metabolism*
  • Neurons / pathology
  • Primary Cell Culture
  • Social Behavior
  • Synapses / metabolism*
  • Synapses / pathology

Substances

  • ANK2 protein, human
  • Ankyrins
  • Neural Cell Adhesion Molecule L1