Abstract
Memory formation in the brain is thought to be depending upon long lasting plastic changes of synaptic contacts that require alterations on the transcriptional level. Here, we characterize LAPSER1, a putative cytokinetic tumor suppressor that binds directly to ProSAP2/Shank3 and the synaptic Rap-Gap protein SPAR1 as a novel postsynaptic density component. Postsynaptic LAPSER1 is in complex with all important members of the canonical Wnt pathway including beta-catenin. Upon N-methyl-D-aspartate receptor-dependent activation, LAPSER1 and beta-catenin comigrate from the postsynaptic density to the nucleus and induce the transcription and translation of known beta-catenin target genes, including Tcfe2a and c-Myc. The nuclear export and cytoplasmic redistribution of beta-catenin is tightly regulated by LAPSER1. We postulate a postsynaptic cross-talk between N-methyl-D-aspartate receptors and a LAPSER1-beta-catenin complex that results in a self-regulated, synaptic activity-dependent expression of beta-catenin target genes. This calls for a novel role of Tcfe2a and c-Myc in plastic changes of neural tissue.
Highlights
Recent studies have demonstrated that newly identified PSD4 molecules like Abi-1 [8], AIDA-1 [9], and Jacob [10] take part in activity-dependent synapse-to-nucleus shuttling, being good candidates for the proposed synaptically activated second messengers and transcription factors involved in long lasting forms of synaptic plasticity [11]
We found that LAPSER1 is highly expressed in brain and localizes to the postsynaptic compartment interacting with the PDZ domain of ProSAP2/Shank3, an important member of the ProSAP/Shank family of scaffolding proteins [23,24,25,26]
This enrichment was as significant as the enrichment of the known PSD proteins SPAR1 and ProSAP2/Shank3
Summary
Recent studies have demonstrated that newly identified PSD4 molecules like Abi-1 [8], AIDA-1 [9], and Jacob [10] take part in activity-dependent synapse-to-nucleus shuttling, being good candidates for the proposed synaptically activated second messengers and transcription factors involved in long lasting forms of synaptic plasticity [11]. Using specific LAPSER1 antibodies in coimmunoprecipitation experiments of rat brain lysate revealed that ProSAP2/Shank3 and SPAR1 are readily detectable within the precipitate (Fig. 2C).
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