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Vol. 16, Issue 1, 128-140, January 2005

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Genetic Analysis of the Neuronal and Ubiquitous AP-3 Adaptor Complexes Reveals Divergent Functions in Brain

E. Seong ^*, B. H. Wainer , E. D. Hughes , T. L. Saunders , M. Burmeister ^* , and V. Faundez  ^|| ¶

^* Mental Health Research Institute and Neuroscience Program, University of Michigan, Ann Arbor, MI 48109; Department of Internal Medicine and Transgenic Animal Model Core, University of Michigan, Ann Arbor, MI 48109; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322; ^|| Department of Cell Biology, Emory University, Atlanta, GA 30322; and ^¶ Department of Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322

Submitted October 13, 2004; Revised November 1, 2004; Accepted November 2, 2004
Monitoring Editor: Sandra Schmid

Neurons express adaptor (AP)-3 complexes assembled with either ubiquitous (3A) or neuronal-specific (3B) 3 isoforms. However, it is unknown whether these complexes indeed perform distinct functions in neuronal tissue. Here, we explore this hypothesis by using genetically engineered mouse models lacking either 3A- or 3B-containing AP-3 complexes. Somatic and neurological phenotypes were specifically associated with the ubiquitous and neuronal adaptor deficiencies, respectively. At the cellular level, AP-3 isoforms were localized to distinct neuronal domains. 3B-containing AP-3 complexes were preferentially targeted to neuronal processes. Consistently, 3B deficiency compromised synaptic zinc stores assessed by Timm's staining and the synaptic vesicle targeting of membrane proteins involved in zinc uptake (ZnT3 and ClC-3). Surprisingly, despite the lack of neurological symptoms, 3A-deficient mouse brain possessed significantly increased synaptic zinc stores and synaptic vesicle content of ZnT3 and ClC-3. These observations indicate that the functions of 3A- and 3B-containing complexes are distinct and divergent. Our results suggest that concerted nonredundant functions of neuronal and ubiquitous AP-3 provide a mechanism to control the levels of selected membrane proteins in synaptic vesicles.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Corresponding authors. E-mail addresses: margit{at}umich.edu; faundez{at}cellbio.emory.edu.

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