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Title: Ring finger protein 10 is a novel synaptonuclear messenger encoding activation of NMDA receptors in hippocampus}
Article:
Abstract:
Synapses and nuclei are connected by bidirectional communication mechanisms that enable information transfer encoded by macromolecules. Here, we identified RNF10 as a novel synaptonuclear protein messenger. RNF10 is activated by calcium signals at the postsynaptic compartment and elicits discrete changes at the transcriptional level. RNF10 is enriched at the excitatory synapse where it associates with the GluN2A subunit of NMDA receptors( NMDARs). Activation of synaptic GluN2A-containing NMDARs and induction of long term potentiation( LTP) lead to the translocation of RNF10 from dendritic segments and dendritic spines to the nucleus. In particular, we provide evidence for importin-dependent long-distance transport from synapto-dendritic compartments to the nucleus. Notably, RNF10 silencing prevents the maintenance of LTP as well as LTP-dependent structural modifications of dendritic spines.
Introduction:
Understanding how local synaptic events are translated into changes in gene expression is a crucial question in neuroscience. Synapses and nuclei are efficiently connected by bidirectional communication routes that enable transfer of information( Fainzilber et al., 2011; Panayotis et al., 2015) and regulate the transcription of genes associated with long-term structural changes of neuronal excitability( Karpova et al., 2012). NMDAR activation plays a key role in this regard( Hardingham and Bading, 2010). NMDARs are heteromeric ionotropic channels that are essential for excitatory neurotransmission( Paoletti et al., 2013; Sanz-Clemente et al., 2013). NMDARs differ in their subunit composition and, in the forebrain, they can be either di- or tri-heteromeric tetramers consisting of two GluN1 and either one or two GluN2A or GluN2B subunits( Paoletti et al., 2013). GluN2A-containing NMDARs are mainly localized at the postsynaptic membrane, at the core of the postsynaptic density( PSD), while the GluN2B-containing NMDARs are also prominently present at extrasynaptic sites( Hardingham and Bading, 2010). In addition, numerous reports have indicated that GluN2A- and GluN2B-containing NMDARs may play different roles in the modulation of synaptic plasticity and in central nervous system( CNS) disorders( Paoletti et al., 2013). These differences in receptor function are probably linked to the cytoplasmic C-tail of the two subunits, which are fairly different and contain specific motifs that bind to PSD-associated scaffolding proteins and to proteins involved in the downstream signal transduction of receptor activation( Sanz-Clemente et al., 2013; Sun et al., 2016). It is generally accepted that rises in synaptic, somatic and nuclear Ca2+ rapidly regulate gene expression by Ca2+-sensing mechanisms( Bading, 2013). Recent work showed that following a fast genomic response to sustained rises in Ca2+, a considerably slower process that depends on the nuclear import of proteins released from synapses couples local synaptic events to more specific gene expression programs( Jordan and Kreutz, 2009; Ch'ng and Martin, 2011; Karpova et al., 2012). The classical active nuclear import pathway involves the binding of importin α isoforms to nuclear localization signal( NLS) bearing cargo proteins. Interestingly, neuronal importins are present at synapses in association with NMDARs and the PSD( Dieterich et al., 2008; Jeffrey et al., 2009) and they are able to translocate to the nucleus in response to NMDAR activation( Thompson et al., 2004; Dieterich et al., 2008). Proteomic studies have identified many proteins in purified synaptosomes that contain a NLS domain, and in the past 10 years, an impressive number of potential synaptonuclear messenger proteins have been characterized( Ch'ng et al., 2012; Karpova et al., 2013; Kaushik et al., 2014). Many of these proteins contain a bona fide NLS and, in some cases, their binding with importin α was shown to be essential for long-distance transport as importin α can serve as an adaptor for nuclear trafficking of cargo in association with a dynein motor( Karpova et al., 2012; Ch'ng et al., 2012). In recent studies, it was shown that Jacob, a Caldendrin-binding protein abundantly expressed in limbic brain and cortex( Dieterich et al., 2008), encodes and transduces the synaptic and extrasynaptic origin of GluN2B-containing NMDAR signals to the nucleus and elicits the divergent transcriptional responses after activation of these receptors( Dieterich et al., 2008; Karpova et al., 2013). These findings point to the fascinating possibility that specific NMDAR signals are encoded at synaptic sites and decoded in the nucleus by long-distance trafficking of protein messengers. Here, we identified Ring Finger protein 10( RNF10; Seki et al., 2000) as a novel synaptonuclear protein messenger, localized at the PSD and specifically associated to the cytoplasmic tail of GluN2A but not GluN2B subunit of NMDARs. After stimulation of synaptic GluN2A-containing NMDARs, RNF10 binds to importin α1 for nuclear long-distance transport. Notably, we show that long-term potentiation( LTP) induces nuclear translocation of RNF10, its interaction with the transcription factor Meox2 and the modulation of gene expression. Most interestingly, RNF10-regulated gene expression appears to feed back to synaptic function.
Discussion:
This report describes a novel synapse-to-nucleus signaling pathway that specifically links activation of synaptic GluN2A-containing NMDARs to nuclear gene expression. We demonstrate that RNF10 is highly expressed in the nucleus as well as at synapses, where it is part of the NMDAR complex and directly interacts with the cytoplasmic tail of the GluN2A subunit of NMDARs. RNF10 dissociates from the NMDAR complex in an activity-dependent manner and we provide compelling evidence for the importin-dependent long-distance transport from synapto-dendritic compartments to the nucleus. The intracellular C-terminal domain of GluN2A contains several target sequences for downstream signaling and scaffolding molecules( Sanz-Clemente et al., 2013; Sun et al., 2016). Among others, RNF10 and CaM share the same GluN2A binding region( aa 991–1029; Bajaj et al., 2014). Our results indicate a preferential formation of RNF10/GluN2A complex in resting conditions that is disrupted in favor of CaM/GluN2A complex following synaptic activity-dependent calcium influx. Overall, our data show that RNF10 binding to GluN2A plays a key role for RNF10 anchoring at the excitatory synapse but also interfere with the formation of CaM/NMDAR complex. Moreover, the presence of RNF10 in close proximity to the receptor channel allows for a rapid calcium-dependent dissociation of RNF10/GluN2A complex following NMDAR activation and for the subsequent formation of RNF10/importin complex. Here, we show that interaction of RNF10 with importin α1 represents a key step for its nuclear translocation. However, we also describe that RNF10 can interact with the majority of importin α isoforms including the importin α5 previously described to be associated with the NMDAR complex( Jeffrey et al., 2009). Taken together, these findings suggest that synaptonuclear trafficking of RNF10 is involved in the control of gene expression, which is necessary for LTP-type synaptic plasticity in hippocampal neurons. Very few studies are available addressing the role of RNF10 in the CNS, and they mainly address its association with the transcription factor Meox2, which regulates cell proliferation and differentiation( Seki et al., 2000; Lin et al., 2005; Hoshikawa et al., 2008; Malik et al., 2013). A very recent study performed in P19 carcinoma cell line and in mouse cerebellar granule cells suggests that RNF10 acts as a positive regulator of neuronal differentiation, as its knockdown reduced the number of cells expressing early and late neuronal markers( Malik et al., 2013). Notably, microarray, subsequent real-time PCR and western blotting analysis allowed us to find, among others, novel RNF10 target genes known to be involved in the regulation of the excitatory synapse function and morphology( Vogt et al., 2007; Michaluk et al., 2011; Bagni et al., 2012; Ramakers et al., 2012; Pavlowsky et al., 2012). RNF10 silencing induced a dramatic up-regulation of MMP9 expression and a concomitant reduction of Arhgef6, ArhGap4 and Ophn1 levels. Intriguingly, all these genes are mutated or dysregulated in intellectual disability syndromes in humans and/or in the corresponding mouse models( Vogt et al., 2007; Michaluk et al., 2011; Ramakers et al., 2012), which are characterized by various alterations in dendritic spines, thus suggesting a key role in synaptic effects observed following RNF10 silencing. In this view, modulation of RNF10 expression in hippocampal neurons demonstrated its relevant role in regulating dendritic spine morphology under resting conditions as well as following activity-dependent plasticity. In particular, RNF10 silencing leads to a significant decrease in spine density that is fully rescued by co-transfection of shRNA-resistant RNF10 construct. As a direct consequence of this dramatic morphological event, we also observe a concomitant reduction in the expression of proteins almost exclusively localized at the excitatory PSD, such as PSD-95, AMPARs GluA1 subunit and NMDARs GluN2A subunit. Notably, overexpression of the RNF10( 1–611) construct unable to translocate to nucleus leads to a significant reduction in PSD-95 positive puncta along dendrites. This result strongly indicates that an impaired RNF10-mediated synaptonuclear signaling and not a reduction of RNF10 synaptic levels is responsible for the reduction of dendritic spine density observed following RNF10 silencing. The present and other studies indicate that NMDAR complex is likely a very rich source of protein messengers that are capable of trafficking to the nucleus. Most important, the present study provides convincing evidence that different NMDAR signals will indeed induce the nuclear import of different messengers. Several reports have documented that NMDARs activation leads to a differential modulation of nuclear gene expression, depending upon their localization( Hardingham and Bading, 2010). In general, activation of synaptic NMDARs promotes the expression of synaptic plasticity-related genes, whereas activation of extrasynaptic NMDARs has been correlated to CNS pathological conditions( Hardingham and Bading, 2010). The protein messenger Jacob, following long-distance transport and nuclear import, can encode and transduce the synaptic and extrasynaptic origin of GluN2B NMDAR signals to the nucleus and might dock a NMDA-receptor-derived signalosome to nuclear target sites in a stimulus-dependent manner( Karpova et al., 2013). Notably, here we show that activation of synaptic but not extrasynaptic NMDARs leads to an increase in RNF10 nuclear localization. Similarly to what was previously described for Jacob( Behnisch et al., 2011), we observe that RNF10 moves to the nucleus after induction of LTP but not LTD, modulating the expression of Meox2 target genes. However, in contrast to Jacob, inhibition of GluN2A- but not GluN2B-containing NMDARs is sufficient to block RNF10 trafficking to the nucleus, its interaction with the transcription factor Meox2 and the expression of the Meox2 target gene p21WAF1/cip1. Another intriguing finding includes the observation that the transcription factor CREB2 also known as ATF4 transits to the nucleus only after induction of NMDAR-dependent cLTD but not cLTP( Lai et al., 2008). Transcriptional regulators at synaptic sites like CRTC1 can also be phosphorylated by synaptic signals in a complex manner and translocation of CRTC1 to the nucleus might link specific types of stimuli to specific changes in gene expression. Overall our data together with the findings from other recent reports( Kaushik et al., 2014; Rishal and Fainzilber, 2014; Panayotis et al., 2015), suggest that synapse-to-nucleus protein transport provide specific ways to inform the nucleus about very different types of synaptic activity. In this context, RNF10 represents a novel synaptonuclear protein messenger responsible for long-lasting re-shaping of dendritic spines as observed after specific synaptic stimuli and required for postsynaptic modifications needed to convey LTP induction.
Brain activity depends on the communication between neurons . This process takes place at the junctions between neurons , which are known as synapses , and typically involves one of the cells releasing a chemical messenger that binds to receptors on the other cell . The binding triggers a cascade of events inside the recipient cell , including the production of new receptors and their insertion into the cell membrane . These changes strengthen the synapse and are thought to be one of the ways in which the brain establishes and maintains memories . However , in order to induce these changes at the synapse , neurons must be able to activate the genes that encode their component parts . These genes are present inside the cell nucleus , which is located some distance away from the synapse . Studies have shown that signals can be sent from the nucleus to the synapse and vice versa , enabling the two parts of the cell to exchange information . Synapses that communicate using a chemical called glutamate have been particularly well studied; but it still remains unclear how the activation of receptors at these “glutamatergic synapses” is linked to activation of genes inside the nucleus at the molecular level . Dinamarca , Guzzetti et al . have now discovered that this process at glutamatergic synapses involves the movement of a protein messenger to the nucleus . Specifically , activation at synapses of a particularly common subtype of receptor , called NMDA , causes a protein called Ring Finger protein 10 ( or RNF10 for short ) to move from the synapse to the nucleus . To leave the synapse , RNF10 first has to bind to proteins called importins , which transport RNF10 into the nucleus . Once inside the nucleus , RNF10 binds to another protein that interacts with the DNA to start the production of new synaptic proteins . Further work is required to identify the molecular mechanisms that trigger RNF10 to leave the synapse . In addition , future studies should evaluate the levels and activity of RNF10 in brain disorders in which synapses are known to function abnormally .