Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 30, Pages 15262-15271Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1904348116
Keywords
nonsyndromic autism; ANK2; giant ankyrin-B; axon branching; L1CAM
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Funding
- Howard Hughes Medical Institute
- George Barth Geller endowed professorship
- National Institutes of Health [R21MH115155, F31NS096848, MH112883, K01 AG041211, P41 EB015897]
- Khan family grant
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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 1:1 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 ankBdeficiency/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.
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