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Ubiquitination-dependent mechanisms regulate synaptic growth and function

Nature volume 412, pages 449–452 (2001)Cite this article

Abstract

The covalent attachment of ubiquitin to cellular proteins is a powerful mechanism for controlling protein activity and localization1. Ubiquitination is a reversible modification promoted by ubiquitin ligases and antagonized by deubiquitinating proteases2. Ubiquitin-dependent mechanisms regulate many important processes including cell-cycle progression, apoptosis and transcriptional regulation3. Here we show that ubiquitin-dependent mechanisms regulate synaptic development at the Drosophila neuromuscular junction (NMJ). Neuronal overexpression of the deubiquitinating protease fat facets4 leads to a profound disruption of synaptic growth control; there is a large increase in the number of synaptic boutons, an elaboration of the synaptic branching pattern, and a disruption of synaptic function. Antagonizing the ubiquitination pathway in neurons by expression of the yeast deubiquitinating protease UBP2 (ref. 5) also produces synaptic overgrowth and dysfunction. Genetic interactions between fat facets and highwire6, a negative regulator of synaptic growth that has structural homology to a family of ubiquitin ligases, suggest that synaptic development may be controlled by the balance between positive and negative regulators of ubiquitination.

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Figure 1: Neuronal overexpression of fat facets leads to synaptic overgrowth.
Figure 2: Neuronal overexpression of fat facets impairs synaptic transmission.
Figure 3: Neuronal overexpression of the yeast deubiquitinating protease UBP2 phenocopies neuronal overexpression of faf.
Figure 4: Loss-of-function mutations in fat facets suppress highwire.

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Acknowledgements

We would like to thank J. Fischer and K. Zinn for their gifts of reagents. This work was supported by the NIH and HHMI (C.S.G.), NSERC Canada (A.P.H.), and the Burroughs-Wellcome Career Award, HHMI, and Whitehall Foundation (A.D.).

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Authors and Affiliations

  1. Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 S. Euclid, Campus Box 8103, St Louis, 63110, Missouri, USA

    Aaron DiAntonio, Scott L. Portman & Andrew M. Amaranto

  2. Department of Molecular and Cell Biology, University of California, Berkeley, Room 509 Life Sciences Addition, Berkeley, 94720, California, USA

    Ali P. Haghighi, Jason D. Lee & Corey S. Goodman

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  1. Aaron DiAntonio
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Correspondence to Aaron DiAntonio.

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DiAntonio, A., Haghighi, A., Portman, S. et al. Ubiquitination-dependent mechanisms regulate synaptic growth and function. Nature 412, 449–452 (2001). https://doi.org/10.1038/35086595

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