In addition to the pathways outlined above, some transmembrane and scaffolding proteins have been implicated in synapse-to-nucleus communication in recent years (Figure 22.1C). First, the C-terminal part of the synaptic scaffolding protein CASK has been shown to translocate to the nucleus16. Nuclear CASK binds to a specific DNA sequence (the T-element) in a complex with the transcription factor TBR1 and the histone-associated protein CINAP17. These three proteins are thought to form a complex involved in nucleosome assembly to allow for Tbr-1 induced transcription of T-element containing genes with CASK acting as a coactivator of Tbr-116-18. More than 20 identified genes containing the nonpalindromic T-element in the 5' regulatory region were found to be expressed in brain17,18. Gene targets for this transcription-inducing complex include the NMDAR1 and NMDAR2B receptors, reelin, the glycine transporter, and the interleukin 7 receptor (Figure 22.1C). More recently also the intracellular domain (ICD) of Neuregulin-1 was shown to translocate to the nucleus and to regulate PSD-95 transcription in an activity-dependent manner in cochlear afferent cells19. The Neuregulin-1-ICD enhances the transcriptional activity of the PSD-95 gene promoter by binding to the zinc-finger transcription factor Eos19 (Figure 22.1C). This enhancement is facilitated by synaptic activity19. Notably, nuclear Neuregulin-1-ICD-Eos signaling was also shown to operate in cortical and hippocampal primary neurons, which indicates that this signaling pathway is active in a broad range of neurons19.
Interestingly, also the cell-surface receptor Notch, that is involved in cell-cell interaction that allow neighboring cells to adopt different fates during development, seems to be associated with synapse-to-nucleus communication (Figure 22.1C). Notch has been localized to synaptic membranes and it was suggested to contribute to synaptic function20. During the differentiation of cortical neurons the ICD of Notch is cleaved via y-secretase activity and translocates to the nucleus, where it binds to the nuclear cofactor CSL (CBF1/RBP-jK^Su(H)/Lag-1)20. Moreover, the modulation of gene transcription mediated by the Notch ICD can be potentiated via activation of CaMKIV pathway21. Of particular interest is the finding that the nuclear accumulation of Notch's ICD promotes dendritic branching and inhibits dendritic growth during neuronal development20. Interestingly, mice with reduced Notch levels have significantly decreased basal and stimulation-induced NF-kB activity and show impaired LTP at hippocampal CA1 synapses22. Whether these two findings are causally related and whether the nuclear accumulation of Notch's ICD plays a role for these phenotypes is currently unknown. In addition, it remains to be established whether a direct link exists between plastic events at the synapse and a Notch synapse-to-nucleus pathway in mature neurons. In this context it should be mentioned that also the ICD of APP23 and the ErbB-4 receptor tyrosine kinase24 translocate to the cell nucleus after cleavage by y-secretase. Both proteins have been localized to synapses, but it is not known at present whether a nuclear translocation occurs in neurons.
Most intriguing, also components of the classical nuclear import pathway, the a-importins, which bind the NLS that is essential for the nuclear import of larger proteins, have recently been shown to translocate from dendrites to the nucleus in an NMDA-receptor-dependent manner25 (Figure 22.1C). Although these findings are at first glance isolated, the emerging picture suggests that a steadily growing number of molecules with a signaling function in the synapto-dendritic compartment also have a specific regulatory role in gene transcription. This role usually requires proteolytical cleavage of the protein and a translocation mechanism, which might be correlated to the activity-dependent nuclear import of a-importins25. In this scenario sustained synaptic activation would trigger nuclear gene transcription not only by classical intracellular messenger pathways but also by the import of protein fragments of synaptic molecules. Interestingly, numerous gene targets regulated by these translocation events encode for synaptic proteins17-19.
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