Genetic analysis of the neuronal and ubiquitous AP-3 adaptor complexes reveals divergent functions in brain.
Neurons express adaptor (AP)-3 complexes assembled with either ubiquitous (beta3A) or neuronal-specific (beta3B) beta3 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 beta3A- or beta3B-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. beta3B-containing AP-3 complexes were preferentially targeted to neuronal processes. Consistently, beta3B 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, beta3A-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 beta3A- and beta3B-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.
Seong
E
E
Mental Health Research Institute and Neuroscience Program, University of Michigan, Ann Arbor, MI 48109, USA.
Wainer
B H
BH
Hughes
E D
ED
Saunders
T L
TL
Burmeister
M
M
Faundez
V
V
D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D000483:Alleles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism; D018390:Gene Targeting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D026901:Membrane Transport Proteins / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D020033:Protein Isoforms; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D015032:Zinc / Q000737:chemistry
C439973:AP3B1 protein, human; D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; D025801:Ubiquitin; D015032:Zinc