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

Abstract

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.

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Acknowledgements

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).

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Authors

Contributions

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.

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Correspondence to Bryen A Jordan.

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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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Jordan, B., Fernholz, B., Khatri, L. et al. Activity-dependent AIDA-1 nuclear signaling regulates nucleolar numbers and protein synthesis in neurons. Nat Neurosci 10, 427–435 (2007). https://doi.org/10.1038/nn1867

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