TORC1 regulation of dendrite regrowth after pruning is linked to actin and exocytosis.

Neurite pruning and regrowth are important mechanisms to adapt neural circuits to distinct developmental stages. Neurite regrowth after pruning often depends on differential regulation of growth signaling pathways, but their precise mechanisms of action during regrowth are unclear. Here, we show that the PI3K/TORC1 pathway is required for dendrite regrowth after pruning in Drosophila peripheral neurons during metamorphosis. TORC1 impinges on translation initiation, and our analysis of 5' untranslated regions (UTRs) of remodeling factor mRNAs linked to actin suggests that TOR selectively stimulates the translation of regrowth over pruning factors. Furthermore, we find that dendrite regrowth also requires the GTPase RalA and the exocyst complex as regulators of polarized secretion, and we provide evidence that this pathway is also regulated by TOR. We propose that TORC1 coordinates dendrite regrowth after pruning by coordinately stimulating the translation of regrowth factors involved in cytoskeletal regulation and secretion.

Energy metabolic pathways in neuronal development and function.

Neuronal development and function are known to be among the most energy-demanding functions of the body. Constant energetic support is therefore crucial at all stages of a neuron's life. The two main adenosine triphosphate (ATP)-producing pathways in cells are glycolysis and oxidative phosphorylation. Glycolysis has a relatively low yield but provides fast ATP and enables the metabolic versatility needed in dividing neuronal stem cells. Oxidative phosphorylation, on the other hand, is highly efficient and therefore thought to provide most or all ATP in differentiated neurons. However, it has recently become clear that due to their distinct properties, both pathways are required to fully satisfy neuronal energy demands during development and function. Here, we provide an overview of how glycolysis and oxidative phosphorylation are used in neurons during development and function.

AMPK adapts metabolism to developmental energy requirement during dendrite pruning in Drosophila.

To reshape neuronal connectivity in adult stages, Drosophila sensory neurons prune their dendrites during metamorphosis using a genetic degeneration program that is induced by the steroid hormone ecdysone. Metamorphosis is a nonfeeding stage that imposes metabolic constraints on development. We find that AMP-activated protein kinase (AMPK), a regulator of energy homeostasis, is cell-autonomously required for dendrite pruning. AMPK is activated by ecdysone and promotes oxidative phosphorylation and pyruvate usage, likely to enable neurons to use noncarbohydrate metabolites such as amino acids for energy production. Loss of AMPK or mitochondrial deficiency causes specific defects in pruning factor translation and the ubiquitin-proteasome system. Our findings distinguish pruning from pathological neurite degeneration, which is often induced by defects in energy production, and highlight how metabolism is adapted to fit energy-costly developmental transitions.