The postsynaptic adenomatous polyposis coli (APC) multiprotein complex is required for localizing neuroligin and neurexin to neuronal nicotinic synapses in vivo.
Synaptic efficacy requires that presynaptic and postsynaptic specializations align precisely and mature coordinately. The underlying mechanisms are poorly understood, however. We propose that adenomatous polyposis coli protein (APC) is a key coordinator of presynaptic and postsynaptic maturation. APC organizes a multiprotein complex that directs nicotinic acetylcholine receptor (nAChR) localization at postsynaptic sites in avian ciliary ganglion neurons in vivo. We hypothesize that the APC complex also provides retrograde signals that direct presynaptic active zones to develop in register with postsynaptic nAChR clusters. In our model, the APC complex provides retrograde signals via postsynaptic neuroligin that interacts extracellularly with presynaptic neurexin. S-SCAM (synaptic cell adhesion molecule) and PSD-93 (postsynaptic density-93) are scaffold proteins that bind to neuroligin. We identify S-SCAM as a novel component of neuronal nicotinic synapses. We show that S-SCAM, PSD-93, neuroligin and neurexin are enriched at alpha3*-nAChR synapses. PSD-93 and S-SCAM bind to APC and its binding partner beta-catenin, respectively. Blockade of selected APC and beta-catenin interactions, in vivo, leads to decreased postsynaptic accumulation of S-SCAM, but not PSD-93. Importantly, neuroligin synaptic clusters are also decreased. On the presynaptic side, there are decreases in neurexin and active zone proteins. Further, presynaptic terminals are less mature structurally and functionally. We define a novel neural role for APC by showing that the postsynaptic APC multiprotein complex is required for anchoring neuroligin and neurexin at neuronal synapses in vivo. APC human gene mutations correlate with autism spectrum disorders, providing strong support for the importance of the association, demonstrated here, between APC, neuroligin and neurexin.
Rosenberg
Madelaine M
MM
Department of Neuroscience, Tufts University, Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts 02111, USA.
Yang
Fang
F
Mohn
Jesse L
JL
Storer
Elizabeth K
EK
Jacob
Michele H
MH
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000818:Animals; D030161:Avian Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002642:Chick Embryo; D046912:Multiprotein Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D017729:Presynaptic Terminals / Q000502:physiology; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; D030161:Avian Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; D051176:beta Catenin