Agrin regulates CLASP2-mediated capture of microtubules at the neuromuscular junction synaptic membrane

Nadine Schmidt, Sreya Basu, Stefan Sladecek, Sabrina Gatti, Jeffrey van Haren, Susan Treves, Jan Pielage, Niels Galjart*, Hans Rudolf Brenner*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

47 Citations (Scopus)
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Abstract

Agrin is the major factor mediating the neuronal regulation of postsynaptic structures at the vertebrate neuromuscular junction, but the details of how it orchestrates this unique three-dimensional structure remain unknown. Here, we show that agrin induces the formation of the dense network of microtubules in the subsynaptic cytoplasm and that this, in turn, regulates acetylcholine receptor insertion into the postsynaptic membrane. Agrin acted in part by locally activating phosphatidylinositol 3-kinase and inactivating GSK3β, which led to the local capturing of dynamic microtubules at agrin-induced acetylcholine receptor (AChR) clusters, mediated to a large extent by the microtubule plus-end tracking proteins CLASP2 and CLIP-170. Indeed, in the absence of CLASP2, microtubule plus ends at the subsynaptic muscle membrane, the density of synaptic AChRs, the size of AChR clusters, and the numbers of subsynaptic muscle nuclei with their selective gene expression programs were all reduced. Thus, the cascade linking agrin to CLASP2-mediated microtubule capturing at the synaptic membrane is essential for the maintenance of a normal neuromuscular phenotype.

Original languageEnglish
Pages (from-to)421-437
Number of pages17
JournalJournal of Cell Biology
Volume198
Issue number3
DOIs
Publication statusPublished - 6 Aug 2012

Research programs

  • EMC MGC-02-13-02

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