Abstract
Neurexins (NXs) and neuroligins (NLs) are cell adhesion molecules that are localized at opposite sites of synaptic membranes. They interact with each other to promote the assembly, maintenance, and function of synapses in the central nervous system. Both NX and NL are cleaved from a membrane-attached intracellular domain in an activity-dependent manner, generating the soluble ectodomain of NX or NL. Expression of the NX1 and NX3 genes in the brain appears to be regulated by a schizophrenia-related protein, DISC1. Here, we show that soluble ecto-NX1β can regulate the expression of DISC1 and induce signaling downstream of DISC1. We also show that NL1 binds to a well-characterized DISC1 interaction partner, Kal-7, and this interaction can be compromised by DISC1. Our results indicate that the NX/NL synaptic complex is intrinsically involved in the regulation of DISC1 function, thus contributing to a better understanding of the pathology of schizophrenia.
Highlights
The development and maintenance of synaptic connections are a dynamic process that requires bidirectional interactions between pre- and postsynaptic components
The expression of the NX1 gene appears to be regulated by a DISC1-dependent mechanism [7], and this regulation is important for brain development and function
We investigated whether this regulation might be reciprocal and whether NX might affect the expression of Disc1
Summary
The development and maintenance of synaptic connections are a dynamic process that requires bidirectional interactions between pre- and postsynaptic components. The synaptic adhesion complex neurexin/neuroligin (NX/NL) mediates synapse formation and triggers pre- and postsynaptic signal transduction by recruiting components to developing synapses [1]. Mammals have three NX genes, each with two promoters. DISC1 is a scaffolding protein that plays several roles during many aspects of neural development [8]. DISC1, together with Kal-7 and Rac, forms a multifunctional protein complex, called the DISC1/Kal-7/Rac signalosome, that is important for development of the nervous system [10]. We show that NL1 binds to Kal-7, and alterations in NX-NL interactions lead to disturbances in the DISC1/Kal-7/Rac signalosome, allowing the activation of Rac. The bands were visualized using the Odyssey CLX Infrared Imaging System (Odyssey)
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