Format

Send to

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

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

Author information

1
Department of Cell Biology, Duke University, Durham, NC 27710.
2
Department of Biochemistry, Duke University, Durham, NC 27710.
3
Department of Cell Biology, Duke University, Durham, NC 27710; Kathryn.Walder@duke.edu benne012@mc.duke.edu.
4
Department of Psychology and Neuroscience, Duke University, Durham, NC 27710.
5
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
6
Department of Radiology, Duke University, Durham, NC 27710.
7
Department of Biomedical Engineering, Duke University, Durham, NC 27710.
8
Department of Neurobiology, Duke University, Durham, NC 27710.
9
Department of Pediatrics, Duke University, Durham, NC 27710.
10
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC 27710.

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

Conflict of interest statement

The authors declare no conflict of interest.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center