Activity-dependent AIDA-1 nuclear signaling regulates nucleolar numbers and protein synthesis in neurons

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Neuronal development, plasticity and survival require activity-dependent synapse-to-nucleus signaling. Most studies implicate an activity-dependent regulation of gene expression in this phenomenon. However, little is known about other nuclear functions that are regulated by synaptic activity. Here we show that a newly identified component of rat postsynaptic densities (PSDs), AIDA-1d, can regulate global protein synthesis by altering nucleolar numbers. AIDA-1d binds to the first two postsynaptic density–95/Discs large/zona occludens-1 (PDZ) domains of the scaffolding protein PSD-95 via its C-terminal three amino acids. Stimulation of NMDA receptors (NMDARs), which are also bound to PSD-95, results in a Ca2+-independent translocation of AIDA-1d to the nucleus, where it couples to Cajal bodies and induces Cajal body–nucleolar association. Long-term neuronal stimulation results in an AIDA-1–dependent increase in nucleolar numbers and protein synthesis. We propose that AIDA-1d mediates a link between synaptic activity and control of protein biosynthetic capacity by regulating nucleolar assembly.

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Figure 1: Characteristics of AIDA-1d.
Figure 2: Cellular distribution of eGFP–AIDA-1d.
Figure 3: Mechanism of AIDA-1d nuclear translocation.
Figure 4: AIDA-1d binds PSD-95 and is in a complex with NR1.
Figure 5: The AIDA-1d C-terminal 3 amino acids are required for an interaction with PSD-95 and for a synaptic enrichment, but not for nuclear shuttling.
Figure 6: AIDA-1d expression and neuronal activity results in Cajal body (CB)-nucleolar association.
Figure 7: Activity- and AIDA-1–dependent increase in nucleolar numbers.
Figure 8: AIDA-1 mediates the activity-dependent increase in protein synthesis.


  1. 1

    Deisseroth, K., Mermelstein, P.G., Xia, H. & Tsien, R.W. Signaling from synapse to nucleus: the logic behind the mechanisms. Curr. Opin. Neurobiol. 13, 354–365 (2003).

  2. 2

    West, A.E., Griffith, E.C. & Greenberg, M.E. Regulation of transcription factors by neuronal activity. Nat. Rev. Neurosci. 3, 921–931 (2002).

  3. 3

    Graef, I.A. et al. L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 401, 703–708 (1999).

  4. 4

    Kaltschmidt, C., Kaltschmidt, B. & Baeuerle, P.A. Stimulation of ionotropic glutamate receptors activates transcription factor NF-κB in primary neurons. Proc. Natl. Acad. Sci. USA 92, 9618–9622 (1995).

  5. 5

    Chawla, S., Vanhoutte, P., Arnold, F.J., Huang, C.L. & Bading, H. Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. J. Neurochem. 85, 151–159 (2003).

  6. 6

    Mu, Y., Otsuka, T., Horton, A.C., Scott, D.B. & Ehlers, M.D. Activity-dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors. Neuron 40, 581–594 (2003).

  7. 7

    Warner, J.R. The economics of ribosome biosynthesis in yeast. Trends Biochem. Sci. 24, 437–440 (1999).

  8. 8

    Grummt, I. Life on a planet of its own: regulation of RNA polymerase I transcription in the nucleolus. Genes Dev. 17, 1691–1702 (2003).

  9. 9

    Kelleher, R.J., III, Govindarajan, A., Jung, H.Y., Kang, H. & Tonegawa, S. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467–479 (2004).

  10. 10

    Si, K. et al. A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in aplysia. Cell 115, 893–904 (2003).

  11. 11

    Wu, L. et al. CPEB-mediated cytoplasmic polyadenylation and the regulation of experience-dependent translation of αCaMKII mRNA at synapses. Neuron 21, 1129–1139 (1998).

  12. 12

    Hyson, R.L. & Rubel, E.W. Activity-dependent regulation of a ribosomal RNA epitope in the chick cochlear nucleus. Brain Res. 672, 196–204 (1995).

  13. 13

    Lafarga, M., Andres, M.A., Fernandez-Viadero, C., Villegas, J. & Berciano, M.T. Number of nucleoli and coiled bodies and distribution of fibrillar centres in differentiating Purkinje neurons of chick and rat cerebellum. Anat. Embryol. (Berl.) 191, 359–367 (1995).

  14. 14

    Solovei, I., Grandi, N., Knoth, R., Volk, B. & Cremer, T. Positional changes of pericentromeric heterochromatin and nucleoli in postmitotic Purkinje cells during murine cerebellum development. Cytogenet. Genome Res. 105, 302–310 (2004).

  15. 15

    Schuman, E.M., Dynes, J.L. & Steward, O. Synaptic regulation of translation of dendritic mRNAs. J. Neurosci. 26, 7143–7146 (2006).

  16. 16

    Steward, O. & Falk, P.M. Protein-synthetic machinery at postsynaptic sites during synaptogenesis: a quantitative study of the association between polyribosomes and developing synapses. J. Neurosci. 6, 412–423 (1986).

  17. 17

    Cajal, S.R. Un sencillo metodo de coloracion selectiva del reticulo protoplasmatico y sus effectos en los diversos organos nerviosos de vertebrados e invertebrados. Trab. Lab. Invest. Biol (Madrid) 2, 129–221 (1903).

  18. 18

    Cioce, M. & Lamond, A.I. Cajal bodies: a long history of discovery. Annu. Rev. Cell Dev. Biol. 21, 105–131 (2005).

  19. 19

    Gall, J.G. The centennial of the Cajal body. Nat. Rev. Mol. Cell Biol. 4, 975–980 (2003).

  20. 20

    Zatsepina, O., Baly, C., Chebrout, M. & Debey, P. The step-wise assembly of a functional nucleolus in preimplantation mouse embryos involves the Cajal (coiled) body. Dev. Biol. 253, 66–83 (2003).

  21. 21

    Paushkin, S., Gubitz, A.K., Massenet, S. & Dreyfuss, G. The SMN complex, an assemblyosome of ribonucleoproteins. Curr. Opin. Cell Biol. 14, 305–312 (2002).

  22. 22

    Jordan, B.A. et al. Identification and verification of novel rodent postsynaptic density proteins. Mol. Cell. Proteomics 3, 857–871 (2004).

  23. 23

    Li, K.W. et al. Proteomics analysis of rat brain postsynaptic density. Implications of the diverse protein functional groups for the integration of synaptic physiology. J. Biol. Chem. 279, 987–1002 (2003).

  24. 24

    Peng, J. et al. Semi-quantitative proteomic analysis of rat forebrain postsynaptic density fractions by mass spectrometry. J. Biol. Chem. 279, 21003–21011 (2004).

  25. 25

    Yoshimura, Y. et al. Molecular constituents of the postsynaptic density fraction revealed by proteomic analysis using multidimensional liquid chromatography-tandem mass spectrometry. J. Neurochem. 88, 759–768 (2004).

  26. 26

    Fu, X., McGrath, S., Pasillas, M., Nakazawa, S. & Kamps, M.P. EB-1, a tyrosine kinase signal transduction gene, is transcriptionally activated in the t(1;19) subset of pre-B ALL, which express oncoprotein E2a-Pbx1. Oncogene 18, 4920–4929 (1999).

  27. 27

    Ghersi, E., Noviello, C. & D'Adamio, L. Amyloid-beta protein precursor (AbetaPP) intracellular domain-associated protein-1 proteins bind to AbetaPP and modulate its processing in an isoform-specific manner. J. Biol. Chem. 279, 49105–49112 (2004).

  28. 28

    Jordan, B.A., Fernholz, B.D., Neubert, T.A. & Ziff, E.B. The Dynamic Synapse: Molecular Methods in Ionotropic Receptor Biology (eds. Kittler, J.T. and Moss, S.J.) (CRC/Taylor & Francis, Boca Raton, Florida, 2006).

  29. 29

    Long, J.F. et al. Supramodular structure and synergistic target binding of the N-terminal tandem PDZ domains of PSD-95. J. Mol. Biol. 327, 203–214 (2003).

  30. 30

    Xu, H. & Hebert, M.D. A novel EB-1/AIDA-1 isoform, AIDA-1c, interacts with the Cajal body protein coilin. BMC Cell Biol. 6, 23 (2005).

  31. 31

    McGaugh, J.L. Memory—a century of consolidation. Science 287, 248–251 (2000).

  32. 32

    Krug, M., Lossner, B. & Ott, T. Anisomycin blocks the late phase of long-term potentiation in the dentate gyrus of freely moving rats. Brain Res. Bull. 13, 39–42 (1984).

  33. 33

    Pastalkova, E. et al. Storage of spatial information by the maintenance mechanism of LTP. Science 313, 1141–1144 (2006).

  34. 34

    Reymann, K.G. & Frey, J.U. The late maintenance of hippocampal LTP: requirements, phases, 'synaptic tagging', 'late-associativity' and implications. Neuropharmacology 52, 24–40 (2006).

  35. 35

    Nguyen, P.V., Abel, T. & Kandel, E.R. Requirement of a critical period of transcription for induction of a late phase of LTP. Science 265, 1104–1107 (1994).

  36. 36

    Vickers, C.A., Dickson, K.S. & Wyllie, D.J. Induction and maintenance of late-phase long-term potentiation in isolated dendrites of rat hippocampal CA1 pyramidal neurones. J. Physiol. (Lond.) 568, 803–813 (2005).

  37. 37

    Duffy, C., Teyler, T.J. & Shashoua, V.E. Long-term potentiation in the hippocampal slice: evidence for stimulated secretion of newly synthesized proteins. Science 212, 1148–1151 (1981).

  38. 38

    Fazeli, M.S., Corbet, J., Dunn, M.J., Dolphin, A.C. & Bliss, T.V. Changes in protein synthesis accompanying long-term potentiation in the dentate gyrus in vivo. J. Neurosci. 13, 1346–1353 (1993).

  39. 39

    Frey, S., Schwiegert, C., Krug, M. & Lossner, B. Long-term potentiation induced changes in protein synthesis of hippocampal subfields of freely moving rats: time-course. Biomed. Biochim. Acta 50, 1231–1240 (1991).

  40. 40

    Prieto, J.L. & McStay, B. Nucleolar biogenesis: the first small steps. Biochem. Soc. Trans. 33, 1441–1443 (2005).

  41. 41

    Thompson, K.R. et al. Synapse to nucleus signaling during long-term synaptic plasticity; a role for the classical active nuclear import pathway. Neuron 44, 997–1009 (2004).

  42. 42

    Ossareh-Nazari, B., Bachelerie, F. & Dargemont, C. Evidence for a role of CRM1 in signal-mediated nuclear protein export. Science 278, 141–144 (1997).

  43. 43

    Vissel, B., Krupp, J.J., Heinemann, S.F. & Westbrook, G.L. A use-dependent tyrosine dephosphorylation of NMDA receptors is independent of ion flux. Nat. Neurosci. 4, 587–596 (2001).

  44. 44

    Yang, L. et al. A novel Ca2+-independent signaling pathway to extracellular signal-regulated protein kinase by coactivation of NMDA receptors and metabotropic glutamate receptor 5 in neurons. J. Neurosci. 24, 10846–10857 (2004).

  45. 45

    Nong, Y. et al. Glycine binding primes NMDA receptor internalization. Nature 422, 302–307 (2003).

  46. 46

    Husi, H., Ward, M.A., Choudhary, J.S., Blackstock, W.P. & Grant, S.G. Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat. Neurosci. 3, 661–669 (2000).

  47. 47

    Jean, F. et al. α1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent. Proc. Natl. Acad. Sci. USA 95, 7293–7298 (1998).

  48. 48

    Graham, R.K. et al. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125, 1179–1191 (2006).

  49. 49

    Ura, S., Masuyama, N., Graves, J.D. & Gotoh, Y. Caspase cleavage of MST1 promotes nuclear translocation and chromatin condensation. Proc. Natl. Acad. Sci. USA 98, 10148–10153 (2001).

  50. 50

    Osten, P. et al. Mutagenesis reveals a role for ABP/GRIP binding to GluR2 in synaptic surface accumulation of the AMPA receptor. Neuron 27, 313–325 (2000).

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We thank A. Lamond (Univ of Dundee) and E. Tan (Scripps Institute) for antibodies to p80-coilin and S. De Souza for PSD-95 plasmid. This work was supported by grants from the US National Institutes of Health (to E.B.Z., R01 MH67229, and B.A.J., K01 MH073759-02).

Author information

The study was conceived and carried out in its majority by B.A.J. Purification of PSDs, NLS screen and AIDA-1 constructs were performed by B.A.J and B.D.F. Additional AIDA-1 constructs and viruses were made by L.K. The experiments performed are the result of extensive discussions with and mentorship of E.B.Z. The manuscript was written by B.A.J. and E.B.Z.

Correspondence to Bryen A Jordan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Alignment of AIDA-1 isoform sequences. (PDF 1274 kb)

Supplementary Video 1

Primary hippocampal neurons grown on 6-cm plates containing coverslip bottoms and expressing eGFP–AIDA-1d were placed into an environmental chamber (37 °C and 5% CO2, Carl Zeiss) for 2 h to equilibrate and imaged every 20 s. (MOV 1895 kb)

Supplementary Video 2 (MOV 1044 kb)

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