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


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.

SUBMITTER: Yang R 

PROVIDER: S-EPMC6660793 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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<i>ANK2</i> autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity.

Yang Rui R   Walder-Christensen Kathryn K KK   Kim Namsoo N   Wu Danwei D   Lorenzo Damaris N DN   Badea Alexandra A   Jiang Yong-Hui YH   Yin Henry H HH   Wetsel William C WC   Bennett Vann V  

Proceedings of the National Academy of Sciences of the United States of America 20190708 30


Giant ankyrin-B (ankB) is a neurospecific alternatively spliced variant of <i>ANK2</i>, 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 pl  ...[more]

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