Article

Guidance Receptor Degradation Is Required for Neuronal Connectivity in the Drosophila Nervous System

University of Cambridge, United Kingdom
PLoS Biology (Impact Factor: 11.77). 12/2010; 8(12):e1000553. DOI: 10.1371/journal.pbio.1000553
Source: PubMed

ABSTRACT Author Summary
Brain wiring is determined by genetic and environmental factors, nature and nurture. The Drosophila brain is a model for the genetic basis of brain wiring. The fly visual system in particular is thought to be “hard-wired,” i.e., encoded solely by a genetic program. Some key genes encode the guidance receptors that serve as “wiring” and synaptic connectivity signals. However, it is poorly understood how guidance receptors are spatiotemporally regulated to serve as meaningful synapse formation signals. Indeed, many genes required for brain wiring do not encode the guidance receptors themselves, but rather encode parts of the cell biological machinery that governs their spatiotemporal signaling dynamics. For example, the vesicular ATPase is an intracellular sorting and acidification complex involved in regulating guidance receptor turnover and signaling. The protein V100 is a member of this v-ATPase complex, and in this study we show that mutations in the v100 gene cause brain wiring defects specifically in the adult brain. We further describe a V100-dependent intracellular “sort-and-degrade” mechanism that is required in neurons, and find that when this mechanism is perturbed, it leads to progressive build-up of and aberrant signaling by guidance receptors. These data suggest that a v100-dependent neuronal degradation mechanism provides a cell biological basis for guidance receptor turnover and spatiotemporally controlled dynamics during neural circuit formation.

0 Followers
 · 
138 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Defects in membrane trafficking and degradation are hallmarks of most, and maybe all, neurodegenerative disorders. Such defects typically result in the accumulation of undegraded proteins due to aberrant endosomal sorting, lysosomal degradation, or autophagy. The genetic or environmental cause of a specific disease may directly affect these membrane trafficking processes. Alternatively, changes in intracellular sorting and degradation can occur as cellular responses of degenerating neurons to unrelated primary defects such as insoluble protein aggregates or other neurotoxic insults. Importantly, altered membrane trafficking may contribute to the pathogenesis or indeed protect the neuron. The observation of dramatic changes to membrane trafficking thus comes with the challenging need to distinguish pathological from protective alterations. Here, we will review our current knowledge about the protective and destructive roles of membrane trafficking in neuronal maintenance and degeneration. In particular, we will first focus on the question of what type of membrane trafficking keeps healthy neurons alive in the first place. Next, we will discuss what alterations of membrane trafficking are known to occur in Alzheimer's disease and other tauopathies, Parkinson's disease, polyQ diseases, peripheral neuropathies, and lysosomal storage disorders. Combining the maintenance and degeneration viewpoints may yield insight into how to distinguish when membrane trafficking functions protectively or contributes to degeneration.
    Cellular and Molecular Life Sciences CMLS 11/2012; 70(16). DOI:10.1007/s00018-012-1201-4 · 5.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pruning of unnecessary axons and/or dendrites is crucial for maturation of the nervous system. However, little is known about cell adhesion molecules (CAMs) that control neuronal pruning. In Drosophila, dendritic arborization neurons, ddaCs, selectively prune their larval dendrites. Here, we report that Rab5/ESCRT-mediated endocytic pathways are critical for dendrite pruning. Loss of Rab5 or ESCRT function leads to robust accumulation of the L1-type CAM Neuroglian (Nrg) on enlarged endosomes in ddaC neurons. Nrg is localized on endosomes in wild-type ddaC neurons and downregulated prior to dendrite pruning. Overexpression of Nrg alone is sufficient to inhibit dendrite pruning, whereas removal of Nrg causes precocious dendrite pruning. Epistasis experiments indicate that Rab5 and ESCRT restrain the inhibitory role of Nrg during dendrite pruning. Thus, this study demonstrates the cell-surface molecule that controls dendrite pruning and defines an important mechanism whereby sensory neurons, via endolysosomal pathway, downregulate the cell-surface molecule to trigger dendrite pruning.
    Developmental Cell 08/2014; 30(4):463-478. DOI:10.1016/j.devcel.2014.06.014 · 10.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: SIGNIFICANCE: Lysosomes are organelles in which cellular degradation occurs in a controlled manner, separated from other cellular components. As several pathways terminate in the lysosome, lysosomal dysfunction has a profound impact on cell homeostasis, resulting in manifold pathological situations, including infectious diseases, neurodegeneration, and aging. RECENT ADVANCES: Lysosomal biology demonstrates that in addition to regulating the final steps of catabolic processes, lysosomes are essential up-stream modulators of autophagy and other essential lysosomal pathways. FUTURE DIRECTIONS AND CRITICAL ISSUES: Lysosomal membrane permeabilization offers therapeutic potential in the treatment of cancer, though the molecular regulators of this process remain obscure. This review focuses on recent discoveries in lysosomal function and dysfunction, primarily in in vivo situations.
    Antioxidants & Redox Signaling 11/2011; 17(5):766-74. DOI:10.1089/ars.2011.4405 · 7.67 Impact Factor

Preview (2 Sources)

Download
0 Downloads
Available from