Spatial Regulation of an E3 Ubiquitin Ligase Directs Selective Synapse Elimination

Stereotyped synaptic connectivity can arise both by precise recognition between appropriate partners during synaptogenesis and by selective synapse elimination. The molecular mechanisms that underlie selective synapse removal are largely unknown. We found that stereotyped developmental elimination of synapses in the Caenorhabditis elegans hermaphrodite-specific motor neuron (HSNL) was mediated by an E3 ubiquitin ligase, a Skp1–cullin–F-box (SCF) complex composed of SKR-1 and the F-box protein SEL-10. SYG-1, a synaptic adhesion molecule, bound to SKR-1 and inhibited assembly of the SCF complex, thereby protecting nearby synapses. Thus, subcellular regulation of ubiquitin-mediated protein degradation contributes to precise synaptic connectivity through selective synapse elimination.

[1]  Erin M. Schuman,et al.  Activity-dependent dynamics and sequestration of proteasomes in dendritic spines , 2006, Nature.

[2]  K. Nakayama,et al.  Ubiquitin ligases: cell-cycle control and cancer , 2006, Nature Reviews Cancer.

[3]  Terrance T. Kummer,et al.  Agrin promotes synaptic differentiation by counteracting an inhibitory effect of neurotransmitter. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[4]  C. Garner,et al.  Mechanisms of vertebrate synaptogenesis. , 2005, Annual review of neuroscience.

[5]  F. Gage,et al.  Neurotransmitter Acetylcholine Negatively Regulates Neuromuscular Synapse Formation by a Cdk5-Dependent Mechanism , 2005, Neuron.

[6]  J. Kaplan,et al.  LIN-23-Mediated Degradation of β-Catenin Regulates the Abundance of GLR-1 Glutamate Receptors in the Ventral Nerve Cord of C. elegans , 2005, Neuron.

[7]  J. Kaplan,et al.  The Anaphase-Promoting Complex Regulates the Abundance of GLR-1 Glutamate Receptors in the Ventral Nerve Cord of C. elegans , 2004, Current Biology.

[8]  Timothy Cardozo,et al.  The SCF ubiquitin ligase: insights into a molecular machine , 2004, Nature Reviews Molecular Cell Biology.

[9]  H. Horvitz,et al.  The Caenorhabditis elegans F-box protein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  M. Zhen,et al.  An SCF-like ubiquitin ligase complex that controls presynaptic differentiation , 2004, Nature.

[11]  Aaron DiAntonio,et al.  Ubiquitin-dependent regulation of the synapse. , 2004, Annual review of neuroscience.

[12]  Cornelia I Bargmann,et al.  Synaptic Specificity Is Generated by the Synaptic Guidepost Protein SYG-2 and Its Receptor, SYG-1 , 2004, Cell.

[13]  M. Bear,et al.  Ubiquitination Regulates PSD-95 Degradation and AMPA Receptor Surface Expression , 2003, Neuron.

[14]  Liqun Luo,et al.  Axon Pruning during Drosophila Metamorphosis Evidence for Local Degeneration and Requirement of the Ubiquitin-Proteasome System , 2003, Neuron.

[15]  K. Broadie,et al.  The Ubiquitin Proteasome System Acutely Regulates Presynaptic Protein Turnover and Synaptic Efficacy , 2003, Current Biology.

[16]  Cornelia I. Bargmann,et al.  The Immunoglobulin Superfamily Protein SYG-1 Determines the Location of Specific Synapses in C. elegans , 2003, Cell.

[17]  Aaron DiAntonio,et al.  Ubiquitin and the synapse , 2002, Nature Reviews Neuroscience.

[18]  C. Goodman,et al.  Ubiquitination-dependent mechanisms regulate synaptic growth and function , 2001, Nature.

[19]  M. Nonet,et al.  rpm-1, A Conserved Neuronal Gene that Regulates Targeting and Synaptogenesis in C. elegans , 2000, Neuron.

[20]  M. Zhen,et al.  Regulation of Presynaptic Terminal Organization by C. elegans RPM-1, a Putative Guanine Nucleotide Exchanger with a RING-H2 Finger Domain , 2000, Neuron.

[21]  J. Lichtman,et al.  Synapse Elimination and Indelible Memory , 2000, Neuron.

[22]  M. Zhen,et al.  The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans , 1999, Nature.

[23]  A. Goldberg,et al.  Proteasome inhibitors: valuable new tools for cell biologists. , 1998, Trends in cell biology.

[24]  G. Wu,et al.  sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins. , 1997, Genes & development.

[25]  T. Südhof,et al.  rab3 is a small GTP-binding protein exclusively localized to synaptic vesicles. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Ehlers.  Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system , 2003, Nature neuroscience.

[27]  R. Deshaies.  SCF and Cullin/Ring H2-based ubiquitin ligases. , 1999, Annual review of cell and developmental biology.