Abstract
Pruning that selectively eliminates unnecessary axons/dendrites is crucial for sculpting the nervous system during development. During Drosophila metamorphosis, dendrite arborization neurons, ddaCs, selectively prune their larval dendrites in response to the steroid hormone ecdysone, whereas mushroom body γ neurons specifically eliminate their axon branches within dorsal and medial lobes. However, it is unknown which E3 ligase directs these two modes of pruning. Here, we identified a conserved SCF E3 ubiquitin ligase that plays a critical role in pruning of both ddaC dendrites and mushroom body γ axons. The SCF E3 ligase consists of four core components Cullin1/Roc1a/SkpA/Slimb and promotes ddaC dendrite pruning downstream of EcR-B1 and Sox14, but independently of Mical. Moreover, we demonstrate that the Cullin1-based E3 ligase facilitates ddaC dendrite pruning primarily through inactivation of the InR/PI3K/TOR pathway. We show that the F-box protein Slimb forms a complex with Akt, an activator of the InR/PI3K/TOR pathway, and promotes Akt ubiquitination. Activation of the InR/PI3K/TOR pathway is sufficient to inhibit ddaC dendrite pruning. Thus, our findings provide a novel link between the E3 ligase and the InR/PI3K/TOR pathway during dendrite pruning.
Highlights
The selective removal of unnecessary or exuberant neuronal processes without loss of neurons, referred to as pruning, is a central theme in the maturation of the nervous system during animal development [1]
This ligase complex has four core components—Cullin1, Roc1a, SkpA, and Supernumerary limbs (Slimb)—that promote ddaC dendrite pruning in response to ecdysone. We show that this ligase facilitates ddaC dendrite pruning through regulation of the Insulin Receptor (InR)/PI3K/Target of Rapamycin (TOR) pathway
Akt ubiquitination leads to its degradation and inactivation of the InR/PI3K/TOR pathway, which is required for dendritic pruning
Summary
The selective removal of unnecessary or exuberant neuronal processes without loss of neurons, referred to as pruning, is a central theme in the maturation of the nervous system during animal development [1]. One well-characterized example is pervasive synaptic branch removal in the mammalian neuromuscular system at birth [6]. In invertebrates, such as holometabolous insects Manduca and Drosophila, the nervous systems are extensively remodeled via pruning and apoptosis during metamorphosis, a transition stage between larval and adult forms [2,3]. In the Drosophila central nervous system (CNS), mushroom body (MB) c neurons, serotonergic neurons, and thoracic ventral neurons prune their larval dendrites and/or axons to form the adult neuronal circuits [7,8,9,10]. Despite the wide occurrence and key roles of pruning in the maturing nervous systems, the molecular and cellular mechanisms underlying pruning remain poorly understood in both invertebrates and vertebrates
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