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J. Biol. Chem., Vol. 280, Issue 18, 18015-18024, May 6, 2005

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Evidence That Dystroglycan Is Associated with Dynamin and Regulates Endocytosis^*

Yougen Zhan, Mathieu R. Tremblay¶, Nadia Melian¶, and Salvatore Carbonetto¶||

From the Centre for Research in Neuroscience and the Departments of Neurology and Neurosurgery and ^¶Biology, Montréal General Hospital Research Institute, McGill University, Montréal, Québec H3G 1A4, Canada

Disruption of the dystroglycan gene in humans and mice leads to muscular dystrophies and nervous system defects including malformation of the brain and defective synaptic transmission. To identify proteins that interact with dystroglycan in the brain we have used immunoaffinity purification followed by mass spectrometry (LC/MS-MS) and found that the GTPase dynamin 1 is a novel dystroglycan-associated protein. The -dystroglycan-dynamin 1 complex also included -dystroglycan and Grb2. Overlay assays indicated that dynamin interacts directly with dystroglycan, and immunodepletion showed that only a pool of dynamin is associated with dystroglycan. Dystroglycan was associated and colocalized immunohistochemically with dynamin 1 in the central nervous system in the outer plexiform layer of retina where photoreceptor terminals are found. Endocytosis in neurons is both constitutive, as in non-neural cells, and regulated by neural activity. To assess the function of dystroglycan in the former, we have assayed transferrin uptake in fibroblastic cells differentiated from embryonic stem cells null for both dystroglycan alleles. In wild-type cells, dystroglycan formed a complex with dynamin and codistributed with cortactin at membrane ruffles, which are organelles implicated in endocytosis. Dystroglycan-null cells had a significantly greater transferrin uptake, a process well known to require dynamin. Expression of dystroglycan in null cells by infection with an adenovirus containing dystroglycan reduced transferrin uptake to levels seen in wild-type embryonic stem cells. These data suggest that dystroglycan regulates endocytosis possibly as a result of its interaction with dynamin.

Received for publication, August 23, 2004 , and in revised form, January 26, 2005.

^* This work was supported by grants (to S. C.) from the Canadian Institutes of Health Research, the Muscular Dystrophy Association (United States), and the Canadian ALS Society. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Centre for Research in Neuroscience, McGill University, Montréal General Hospital Research Institute, 1650 Cedar Ave., Montréal, Québec H3G 1A4, Canada. Tel.: 514-934-1934 (ext. 44237); E-mail: sal.carbonetto{at}mcgill.ca.

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