Abstract
Components of the COP9 signalosome (CSN), a key member of the conserved 26S proteasome degradation pathway, have been detected to be altered in patients of several debilitating syndromes. These findings suggest that CSN acts in neural circuits, but the exact function of CSN in brain remains unidentified. Previously, using Drosophila peripheral nervous system (PNS) as a model system, we determined that CSN is a critical regulator of dendritic morphogenesis. We found that defects in CSN led to the strikingly contrast phenotype of either reducing or stimulating dendritic branching. In particular, we have reported that CSN stimulates dendritic branching via Cullin1-mediated proteolysis. Here we describe that CSN inhibits dendritic arborization in PNS neurons acting via control of Cullin3 function: loss of Cullin3 causes excessive dendritic branching. We also identified a downstream target for Cullin3-dependent degradation in neurons – the actin-crosslinking BTB-domain protein Kelch. Inappropriate accumulation of Kelch, either due to the impaired Cullin3-dependent turnover, or ectopic expression of Kelch, leads to uncontrolled dendritic branching. These findings indicate that the CSN pathway modulates neuronal network in a multilayer manner, providing the foundation for new insight into the CSN role in human mental retardation disorders and neurodegenerative disease.
Highlights
The morphological changes in dendritic development are essential for the proper wiring of the brain
Loss of cullin3 stimulates neuronal development Previously we identified that COP9 signalosome (CSN) normally promotes dendritic branching via control of Cullin1 function, and prevents excessive dendritic branching through regulation of the Cullin3-dependent pathways (63)
Larval peripheral nervous system (PNS) neurons at the third instar stage elaborate characteristic, highly branched subepidermal patterns that can be visualized in living embryos or larvae with green fluorescent protein (GFP) [42] (Figure 1)
Summary
The morphological changes in dendritic development are essential for the proper wiring of the brain. Some of these filopodia are stabilized into new dendritic branches, whereas later in development these dynamic filopodial extensions can develop into dendritic spines [1,2]. A large number of disorders of the central nervous system are associated with altered dendritic spine numbers and morphology. These include multiple mental retardation disorders and autism spectrum disorders [4,5,6,7,8]. Changes in the structure and function of dendritic spines contribute to numerous physiological processes such as synaptic transmission and plasticity, as well as behavior including learning and memory [14,15,16]
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