Synaptic Cross-talk between N-Methyl-d-aspartate Receptors and LAPSER1-β-Catenin at Excitatory Synapses

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 ␤-catenin. Upon N-methyl-D-aspartate receptor-dependent activation, LAPSER1 and ␤-catenin comigrate from the postsynaptic density to the nucleus and induce the transcription and translation of known ␤-catenin target genes, including Tcfe2a and c-Myc. The nuclear export and cytoplasmic redistribution of ␤-catenin is tightly regulated by LAPSER1. We postulate a postsynaptic cross-talk between N-methyl-D-aspartate receptors and a LAPSER1-␤-catenin complex that results in a self-regulated, synaptic activity-dependent expression of ␤-catenin target genes. This calls for a novel role of Tcfe2a and c-Myc in plastic changes of neural tissue.Changes in gene expression and protein synthesis leading to alterations in spine and synaptic morphology are believed to be the neurobiological core elements of learning and memory (1-4). These complex neuronal processes require the transport of signals generated at the synapse to the nucleus and their conversion into the transcription of specific genes. This activitydependent synapse-to-nucleus signaling is known to be Ca 2ϩ -dependent and mediated by nucleocytoplasmatic shuttling of transcription factors and/or their regulatory proteins (5-7).Recent studies have demonstrated that newly identified PSD 4 molecules like Abi-1 (8), AIDA-1 (9), and Jacob (10) take part in activity-dependent synapse-to-nucleus shuttling, thus being good candidates for the proposed synaptically activated second messengers and transcription factors involved in long lasting forms of synaptic plasticity (11). Fezzins are a family of PSD proteins (LAPSER1/LZTS2 (12), ProSAPiP1/LZTS3 (13), PSD-Zip70/LZTS1 (14, 15), and N4BP3 (16)) that are able to build homo-and heterooligomers and are defined by a conserved Fez1 domain with hitherto unknown function. LAPSER1 has been initially characterized as a putative tumor suppressor gene according to its ability to inhibit cell growth when overexpressed (12) and has been reported to be involved in cytokinesis colocalizing with centrosomes and interacting with ␥-tubulin and p80 katanin (17). Thyssen et al. (18) showed that LAPSER1 containing various domains of a potential transcription factor can indeed enter the nuclear compartment and interacts with ␤-catenin. Moreover, it is able to influence nuclear localization and signaling of this key molecule of the Wnt/␤-catenin pathway (19). Synaptic ␤-catenin as a well known part of cadherin-mediated cell-cell adhesions at synapses (20, 21) translocates from synapses to the nucleus even without a specific Wnt signal (22). These observations prompted us to investigate the putat...

The spatio‐temporal expression of ProSAP/shank family members and their interaction partner LAPSER1 during Xenopus laevis development

“…Single transfections of these constructs revealed punctate and fibrillar staining patterns reflecting the intracellular localization of these proteins upon overexpression as previously described (Romorini et al, 2004;Thyssen et al, 2006;Proepper et al, 2007;Schmeisser et al, 2009;Grabrucker et al, 2011) (Supp. Fig.…”

“…One of these proteins is LAPSER1, which interacts with the PDZ domain of ProSAP2/Shank3 in rat (Schmeisser et al, 2009). Until now, nothing was known about an interaction of LAPSER1 with members of the ProSAP/Shank family in Xenopus.…”

“…Originally, LAPSER1 was identified as a tumor suppressor gene in human prostate carcinomas (Cabeza-Arvelaiz et al, 2001). The ATEI motif at the Cterminal end of LAPSER1 can physically interact with the PDZ domain of ProSAP2/Shank3 (Schmeisser et al, 2009). Moreover, LAPSER1 is able to form a complex with b-catenin.…”

“…Moreover, LAPSER1 is able to form a complex with b-catenin. By regulating the nuclear export of the latter, LAPSER1 coregulates the transcription of b-catenin target genes such as Tcfe2a and c-myc (Thyssen et al, 2006;Schmeisser et al, 2009).…”

Cognitive flexibility and long-term depression (LTD) are impaired following β-catenin stabilization in vivo

“…β-catenin stabilization was also restricted to adult, differentiated neurons, which are less sensitive to changes in β-catenin levels (37), and much of the available β-catenin was localized to synapses due to its association with cadherin. Finally, nuclear transport of β-catenin may also be more carefully regulated in neurons (38), and levels of Lef1 are relatively low in the hippocampus compared with other brain regions (39), reducing the sensitivity of Wnt signaling to changes in levels of cytoplasmic β-catenin (39).…”