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The nuclear import of Frizzled2-C by Importins-β11 and α2 promotes postsynaptic development

Nature Neuroscience volume 13, pages 935943 (2010) | Download Citation

Abstract

Synapse-to-nucleus signaling is critical for synaptic development and plasticity. In Drosophila, the ligand Wingless causes the C terminus of its Frizzled2 receptor (Fz2-C) to be cleaved and translocated from the postsynaptic density to nuclei. The mechanism of nuclear import is unknown and the developmental consequences of this translocation are uncertain. We found that Fz2-C localization to muscle nuclei required the nuclear import factors Importin-β11 and Importin-α2 and that this pathway promoted the postsynaptic development of the subsynaptic reticulum (SSR), an elaboration of the postsynaptic plasma membrane. importin-β11 (imp-β11) and dfz2 mutants had less SSR, and some boutons lacked the postsynaptic marker Discs Large. These developmental defects in imp-β11 mutants could be overcome by expression of Fz2-C fused to a nuclear localization sequence that can bypass Importin-β11. Thus, Wnt-activated growth of the postsynaptic membrane is mediated by the synapse-to-nucleus translocation and active nuclear import of Fz2-C via a selective Importin-β11/α2 pathway.

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Acknowledgements

We gratefully acknowledge V. Budnik and colleagues for generously providing antibodies and fly stocks and helpful discussions. We thank S. Cotterrill, R. Fleming, I. Kiss, P. Macdonald, B. Mechler, H. Bellen, M. Noll, M. Ramaswami, H. Saumweber, D. Schmucker, G. Struhl, J. Szabad, J.P. Vincent, S. Wasserman, Y. Jan, L. Zipursky, the Bloomington Stock Center and the Developmental Studies Hybridoma Bank for fly stocks and antibodies. We also thank M. Kovtun and members of the Schwarz laboratory for helpful discussions and critical readings of the manuscript, as well as M. Liana and L. Bu of the Intellectual and Developmental Disability Research Center Histology (grant number P30HD18655) and Imaging Cores for technical assistance. This work was supported by US National Institutes of Health grants RO1 NS041062 and MH075058 (T.L.S.) and a predoctoral fellowship from the National Defense Science and Engineering Graduate Foundation (T.J.M.).

Author information

Author notes

    • Timothy J Mosca

    Present address: Stanford University, Department of Biology, Stanford, California, USA.

Affiliations

  1. The F.M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, Massachusetts, USA.

    • Timothy J Mosca
    •  & Thomas L Schwarz
  2. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.

    • Timothy J Mosca
    •  & Thomas L Schwarz

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Contributions

T.J.M. performed the experiments and analyzed the data. T.J.M. and T.L.S. designed the experiments and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Thomas L Schwarz.

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DOI

https://doi.org/10.1038/nn.2593

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