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N-WASP is required for Amphiphysin-2/BIN1-dependent nuclear positioning and triad organization in skeletal muscle and is involved in the pathophysiology of centronuclear myopathy.

Authors :
Falcone S
Roman W
Hnia K
Gache V
Didier N
Lainé J
Auradé F
Marty I
Nishino I
Charlet-Berguerand N
Romero NB
Marazzi G
Sassoon D
Laporte J
Gomes ER
Source :
EMBO molecular medicine [EMBO Mol Med] 2014 Nov; Vol. 6 (11), pp. 1455-75.
Publication Year :
2014

Abstract

Mutations in amphiphysin-2/BIN1, dynamin 2, and myotubularin are associated with centronuclear myopathy (CNM), a muscle disorder characterized by myofibers with atypical central nuclear positioning and abnormal triads. Mis-splicing of amphiphysin-2/BIN1 is also associated with myotonic dystrophy that shares histopathological hallmarks with CNM. How amphiphysin-2 orchestrates nuclear positioning and triad organization and how CNM-associated mutations lead to muscle dysfunction remains elusive. We find that N-WASP interacts with amphiphysin-2 in myofibers and that this interaction and N-WASP distribution are disrupted by amphiphysin-2 CNM mutations. We establish that N-WASP functions downstream of amphiphysin-2 to drive peripheral nuclear positioning and triad organization during myofiber formation. Peripheral nuclear positioning requires microtubule/Map7/Kif5b-dependent distribution of nuclei along the myofiber and is driven by actin and nesprins. In adult myofibers, N-WASP and amphiphysin-2 are only involved in the maintenance of triad organization but not in the maintenance of peripheral nuclear positioning. Importantly, we confirmed that N-WASP distribution is disrupted in CNM and myotonic dystrophy patients. Our results support a role for N-WASP in amphiphysin-2-dependent nuclear positioning and triad organization and in CNM and myotonic dystrophy pathophysiology.<br /> (© 2014 The Authors. Published under the terms of the CC BY 4.0 license.)

Details

Language :
English
ISSN :
1757-4684
Volume :
6
Issue :
11
Database :
MEDLINE
Journal :
EMBO molecular medicine
Publication Type :
Academic Journal
Accession number :
25262827
Full Text :
https://doi.org/10.15252/emmm.201404436