Glial-Derived Prodegenerative Signaling in the Drosophila Neuromuscular System

• Published in: Neuron (Cambridge, Mass.) Mass.), 2011-12, Vol.72 (5), p.760-775
• Main Authors: Keller, Lani C., Cheng, Ling, Locke, Cody J., Müller, Martin, Fetter, Richard D., Davis, Graeme W.
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Apoptotic Protease-Activating Factor 1 - genetics; Apoptotic Protease-Activating Factor 1 - metabolism; Caspases - genetics; Caspases - metabolism; Disease Models, Animal; Drosophila; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Excitatory Postsynaptic Potentials - genetics; Fluorescence Recovery After Photobleaching - methods; Green Fluorescent Proteins - genetics; Insects; Kinases; Mammals; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondria - ultrastructure; Motor Neuron Disease - genetics; Motor Neuron Disease - pathology; Mutation - genetics; Nerve Degeneration - genetics; Nerve Degeneration - pathology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neuroglia - physiology; Neuroglia - ultrastructure; Neuromuscular Junction - genetics; Neuromuscular Junction - metabolism; Neuromuscular Junction - pathology; Neuromuscular Junction - ultrastructure; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; RNA Interference - physiology; Signal Transduction - genetics; Signal Transduction - physiology; Software; Studies
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2011.09.031

We provide evidence for a prodegenerative, glial-derived signaling framework in the Drosophila neuromuscular system that includes caspase and mitochondria-dependent signaling. We demonstrate that Drosophila TNF-α ( eiger) is expressed in a subset of peripheral glia, and the TNF-α receptor (TNFR), Wengen, is expressed in motoneurons. NMJ degeneration caused by disruption of the spectrin/ankyrin skeleton is suppressed by an eiger mutation or by eiger knockdown within a subset of peripheral glia. Loss of wengen in motoneurons causes a similar suppression providing evidence for glial-derived prodegenerative TNF-α signaling. Neither JNK nor NFκβ is required for prodegenerative signaling. However, we provide evidence for the involvement of both an initiator and effector caspase, Dronc and Dcp-1, and mitochondrial-dependent signaling. Mutations that deplete the axon and nerve terminal of mitochondria suppress degeneration as do mutations in Drosophila Bcl-2 ( debcl), a mitochondria-associated protein, and Apaf-1 ( dark), which links mitochondrial signaling with caspase activity in other systems. ► Identification of glial-derived prodegenerative signaling at the Drosophila NMJ ► TNF-α is expressed in peripheral glia and is necessary for neuromuscular degeneration ► The TNF-α receptor is expressed in motoneurons and is necessary for NMJ degeneration ► Mitochondria-dependent signaling participates in prodegenerative mechanism