Abstract
The pre- and postsynaptic membranes comprising the synaptic junction differ in protein composition. The membrane trafficking mechanisms by which neurons control surface polarization of synaptic receptors remain poorly understood. The sorting receptor Sortilin-related CNS expressed 1 (SorCS1) is a critical regulator of trafficking of neuronal receptors, including the presynaptic adhesion molecule neurexin (Nrxn), an essential synaptic organizer. Here, we show that SorCS1 maintains a balance between axonal and dendritic Nrxn surface levels in the same neuron. Newly synthesized Nrxn1α traffics to the dendritic surface, where it is endocytosed. Endosomal SorCS1 interacts with the Rab11 GTPase effector Rab11 family-interacting protein 5 (Rab11FIP5)/Rab11 interacting protein (Rip11) to facilitate the transition of internalized Nrxn1α from early to recycling endosomes and bias Nrxn1α surface polarization towards the axon. In the absence of SorCS1, Nrxn1α accumulates in early endosomes and mispolarizes to the dendritic surface, impairing presynaptic differentiation and function. Thus, SorCS1-mediated sorting in dendritic endosomes controls Nrxn axonal surface polarization required for proper synapse development and function.
Highlights
Neurons are highly compartmentalized cells that need to maintain distinct membrane identities
To determine whether Sortilinrelated CNS expressed 1 (SorCS1) controls the subcellular distribution of endogenous Nrxn, we immunostained Sorcs1flox/flox neurons electroporated with Cre or enhanced green fluorescent protein (EGFP) with a pan-Nrxn antibody directed against the conserved cytoplasmic tail [28] (S1E Fig and S1F Fig), which labels endogenous Nrxn (S1G Fig and S1H Fig)
Our findings suggest that SorCS1 is either required for endocytosis of Nrxn1α or acts in endosomes to bias Nrxn1α surface polarization toward the axon
Summary
Neurons are highly compartmentalized cells that need to maintain distinct membrane identities. This is especially clear at the synapse, where pre- and postsynaptic membranes differ dramatically in their protein composition [1]. Membrane trafficking mechanisms that organize and maintain the polarized distribution of receptor proteins during the formation, maturation, and plasticity of synapses are of key importance for the proper function of neural circuits [2,3]. Neurexins (Nrxns), expressed from 3 genes as α-, β-, and γ-Nrxns, are essential presynaptic adhesion molecules that engage in a network of interactions with multiple pre- and postsynaptic extracellular ligands [4] and act in a cell-type–specific manner to regulate synapse number, function, and plasticity [5,6,7,8,9].
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