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MBC in Press, published online ahead of print November 10, 2004
Mol. Biol. Cell 10.1091/mbc.E04-10-0892

A more recent version of this article appeared on January 1, 2005
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Submitted on October 13, 2004
Revised on November 1, 2004
Accepted on November 2, 2004

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

E. Seong,* B. H. Wainer,{dagger} E. D. Hughes,{ddagger} T. L. Saunders,{ddagger} M. Burmeister,*{sect} and V. Faundez{sect}||¶

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

Monitoring Editor: Sandra Schmid

Neurons express AP-3 complexes assembled with either ubiquitous ({beta}3A) or neuronal-specific ({beta}3B) {beta}3 isoforms. However, it is unknown whether these complexes indeed perform distinct functions in neuronal tissue. Here, we explore this hypothesis using genetically engineered mouse models lacking either {beta}3A- or {beta}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. {beta}3B-containing AP-3 complexes were preferentially targeted to neuronal processes. Consistently, {beta}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, {beta}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 {beta}3A- and {beta}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.

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




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