Abstract
Altered dendritic arborization contributes to numerous physiological processes including synaptic plasticity, behavior, learning and memory, and is one of the most consistent neuropathologic conditions found in a number of mental retardation disorders, schizophrenia, and neurodegenerative disease. COP9 signalosome (CSN), an evolutionarily conserved regulator of the Cullin-based ubiquitin ligases that act in the proteasome pathway, has been found associated with diverse debilitating syndromes, suggesting that CSN may be involved in regulation of dendritic arborization. However, the mechanism of this control, if it exists, is unknown. To address whether the CSN pathway plays a role in dendrites, we used a simple and genetically tractable model, Drosophila larval peripheral nervous system. Our model study identified the COP9 signalosome as the key and multilayer regulator of dendritic arborization. CSN is responsible for shaping the entire dendritic tree through both stimulating and then repressing dendritic branching. We identified that CSN exerts its dualistic function via control of different Cullins. In particular, CSN stimulates dendritic branching through Cullin1, and inhibits it via control of Cullin3 function. We also identified that Cullin1 acts in neurons with the substrate-specific F-box protein Slimb to target the Cubitus interruptus protein for degradation.
Highlights
Dendritic spine morphogenesis is a fundamental part of the process of synapse formation and maturation during brain development
We detected the less and more elaborated dendritic phenotypes (Figure 2F, G). These results indicated that COP9 signalosome (CSN) and Nedd8 act together in dendritic morphogenesis to regulate proteolysis
CSN5 and Nedd8 control dendritic arborization (DA) neurons of different classes In addition to the ddaC neurons, we found that mutations in
Summary
Dendritic spine morphogenesis is a fundamental part of the process of synapse formation and maturation during brain development. Morphological alterations of dendrites and spines occur in Huntington’s disease and in animal models [3,4,5] These data indicate at least an indirect link between spine morphogenesis and disease. Fragile X syndrome is characterized by an increase in dendritic spines with long, thin, immature morphology, suggesting a deficiency in developmental pruning of the spines [6]. It appears that the ‘‘mental disorder neuron’’ has too many or too few, too strong or too weak, excitatory synapses relative to the level of inhibition [8]. These changes may result in suboptimal neuronal network connectivity and, intellectual discapacity
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