Ubiquitination-dependent mechanisms regulate synaptic growth and function

Abstract

The covalent attachment of ubiquitin to cellular proteins is a powerful mechanism for controlling protein activity and localization. Ubiquitination is a reversible modification promoted by ubiquitin ligases and antagonized by deubiquitinating proteases. Ubiquitin-dependent mechanisms regulate many important processes including cell-cycle progression, apoptosis and transcriptional regulation. Here we show that ubiquitin-dependent mechanisms regulate synaptic development at the Drosophila neuromuscular junction (NMJ). Neuronal overexpression of the deubiquitinating protease fat facets 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 highwire, 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.

The ubiquitin-proteasome pathway and synaptic plasticity

“…Overexpression of faf in the developing Drosophila nervous system causes synaptic overgrowth and perturbs synaptic transmission. A similar phenotype is observed when a yeast DUB is expressed in the fruit fly CNS (DiAntonio et al 2001).…”

Multiplex proteomic analysis by two‐dimensional differential in‐gel electrophoresis

“…Ubiquitination has previously been implicated in the cell survival response under conditions of stress, morphogenesis, organogenesis, and exocytosis. It has also been shown to be important in hippocampal long-term potentiation in mice [19] and in the growth of presynaptic nerve terminals in Drosophila [20]. This is interesting because the present studies also showed upregulation of the annexin V protein, which has been shown to have neurotrophic effects on cultured neurons [11].…”

The atypical cadherin flamingo regulates synaptogenesis and helps prevent axonal and synaptic degeneration in Drosophila

“…The following flies were used: fmi E59 , UAS-Fmi, UAS-ÎEx (28), Df(2R)stan 2 , fmi 72 (34), elav-Gal4 (DiAntonio et al, 2001), fmi 1071 and fmi 1127 . fmi mutant alleles and the deficiency line were balanced with CyO KrGFP allowing easy selection of GFP-negative fmi mutant larvae (Gao et al, 2000).…”

“…Other molecules are more directly involved in synaptogenesis, synaptic growth, or maintenance. These molecules include bone morphogenetic protein (Alberle et al, 2002;Marques et al, 2002;Rawson et al, 2003;McCabe et al, 2003;Keshishian and Kim, 2004), ubiquitin (Oh et al, 1994;DiAntonio et al, 2001;Murphey and Godenschwege, 2002;DiAntonio and Hicke, 2004), cell adhesion molecules (Washbourne et al, 2004), and Wingless signaling components (Packard et al, 2003;Charron and Tessier-Lavigne, 2005).…”