Cargando…

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

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 micro...

Descripción completa

Detalles Bibliográficos
Autores principales: Schmidt, Nadine, Basu, Sreya, Sladecek, Stefan, Gatti, Sabrina, van Haren, Jeffrey, Treves, Susan, Pielage, Jan, Galjart, Niels, Brenner, Hans Rudolf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413356/
https://www.ncbi.nlm.nih.gov/pubmed/22851317
http://dx.doi.org/10.1083/jcb.201111130
_version_ 1782240048545005568
author Schmidt, Nadine
Basu, Sreya
Sladecek, Stefan
Gatti, Sabrina
van Haren, Jeffrey
Treves, Susan
Pielage, Jan
Galjart, Niels
Brenner, Hans Rudolf
author_facet Schmidt, Nadine
Basu, Sreya
Sladecek, Stefan
Gatti, Sabrina
van Haren, Jeffrey
Treves, Susan
Pielage, Jan
Galjart, Niels
Brenner, Hans Rudolf
author_sort Schmidt, Nadine
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3413356
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-34133562013-02-06 Agrin regulates CLASP2-mediated capture of microtubules at the neuromuscular junction synaptic membrane Schmidt, Nadine Basu, Sreya Sladecek, Stefan Gatti, Sabrina van Haren, Jeffrey Treves, Susan Pielage, Jan Galjart, Niels Brenner, Hans Rudolf J Cell Biol Research Articles 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. The Rockefeller University Press 2012-08-06 /pmc/articles/PMC3413356/ /pubmed/22851317 http://dx.doi.org/10.1083/jcb.201111130 Text en © 2012 Schmidt et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Schmidt, Nadine
Basu, Sreya
Sladecek, Stefan
Gatti, Sabrina
van Haren, Jeffrey
Treves, Susan
Pielage, Jan
Galjart, Niels
Brenner, Hans Rudolf
Agrin regulates CLASP2-mediated capture of microtubules at the neuromuscular junction synaptic membrane
title Agrin regulates CLASP2-mediated capture of microtubules at the neuromuscular junction synaptic membrane
title_full Agrin regulates CLASP2-mediated capture of microtubules at the neuromuscular junction synaptic membrane
title_fullStr Agrin regulates CLASP2-mediated capture of microtubules at the neuromuscular junction synaptic membrane
title_full_unstemmed Agrin regulates CLASP2-mediated capture of microtubules at the neuromuscular junction synaptic membrane
title_short Agrin regulates CLASP2-mediated capture of microtubules at the neuromuscular junction synaptic membrane
title_sort agrin regulates clasp2-mediated capture of microtubules at the neuromuscular junction synaptic membrane
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413356/
https://www.ncbi.nlm.nih.gov/pubmed/22851317
http://dx.doi.org/10.1083/jcb.201111130
work_keys_str_mv AT schmidtnadine agrinregulatesclasp2mediatedcaptureofmicrotubulesattheneuromuscularjunctionsynapticmembrane
AT basusreya agrinregulatesclasp2mediatedcaptureofmicrotubulesattheneuromuscularjunctionsynapticmembrane
AT sladecekstefan agrinregulatesclasp2mediatedcaptureofmicrotubulesattheneuromuscularjunctionsynapticmembrane
AT gattisabrina agrinregulatesclasp2mediatedcaptureofmicrotubulesattheneuromuscularjunctionsynapticmembrane
AT vanharenjeffrey agrinregulatesclasp2mediatedcaptureofmicrotubulesattheneuromuscularjunctionsynapticmembrane
AT trevessusan agrinregulatesclasp2mediatedcaptureofmicrotubulesattheneuromuscularjunctionsynapticmembrane
AT pielagejan agrinregulatesclasp2mediatedcaptureofmicrotubulesattheneuromuscularjunctionsynapticmembrane
AT galjartniels agrinregulatesclasp2mediatedcaptureofmicrotubulesattheneuromuscularjunctionsynapticmembrane
AT brennerhansrudolf agrinregulatesclasp2mediatedcaptureofmicrotubulesattheneuromuscularjunctionsynapticmembrane