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The Journal of Neuroscience, July 28, 2004, 24(30):6776-6784; doi:10.1523/JNEUROSCI.1826-04.2004

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Cellular/Molecular
Neuronal Nicotinic Synapse Assembly Requires the Adenomatous Polyposis Coli Tumor Suppressor Protein

Murali Krishna Temburni, ^* Madelaine M. Rosenberg, ^* Narendra Pathak, Russell McConnell, and Michele H. Jacob

Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111

Normal cognitive and autonomic functions require nicotinic synaptic signaling. Despite the physiological importance of these synapses, little is known about molecular mechanisms that direct their assembly during development. We show here that the tumor-suppressor protein adenomatous polyposis coli (APC) functions in localizing 3-nicotinic acetylcholine receptors (nAChRs) to neuronal postsynaptic sites. Our quantitative confocal microscopy studies indicate that APC is selectively enriched at cholinergic synapses; APC surface clusters are juxtaposed to synaptic vesicle clusters and colocalize with 3-nAChRs but not with the neighboring synaptic glycine receptors or perisynaptic 7-nAChRs on chick ciliary ganglion (CG) neurons. We identify PSD (postsynaptic density)-93, -catenin, and microtubule end binding protein EB1 as APC binding partners. PSD-93 and -catenin are also enriched at 3-nAChR postsynaptic sites. EB1 shows close proximity to and partial overlap with 3-nAChR and APC surface clusters. We tested the role of APC in neuronal nicotinic synapse assembly by using retroviral-mediated in vivo overexpression of an APC dominant-negative (APC-dn) peptide to block the interaction of endogenous APC with both EB1 and PSD-93 during synapse formation in CG neurons. The overexpressed APC-dn led to dramatic decreases in 3-nAChR surface levels and clusters. Effects were specific to 3-nAChR postsynaptic sites; synaptic glycine receptor and perisynaptic 7-nAChR clusters were not altered. In addition, APC-dn also reduced surface membrane-associated clusters of PSD-93 and EB1. The results show that APC plays a key role in organizing excitatory cholinergic postsynaptic specializations in CG neurons. We identify APC as the first nonreceptor protein to function in localizing nAChRs to neuronal synapses in vivo.

Key words: nicotinic; cholinergic; nAChR; synapse formation; targeting; neuron; ciliary ganglion; adenomatous polyposis coli; APC

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Received Oct 15, 2003; revised June 11, 2004; accepted June 11, 2004.

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