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Featured ArticleResearch Articles, Development/Plasticity/Repair

The GTPase Arl8B Plays a Principle Role in the Positioning of Interstitial Axon Branches by Spatially Controlling Autophagosome and Lysosome Location

Gee Adnan, Aine Rubikaite, Moqadisa Khan, Michael Reber, Philip Suetterlin, Robert Hindges and Uwe Drescher
Journal of Neuroscience 14 October 2020, 40 (42) 8103-8118; DOI: https://doi.org/10.1523/JNEUROSCI.1759-19.2020
Gee Adnan
1Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom
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Aine Rubikaite
1Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom
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Moqadisa Khan
1Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom
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Michael Reber
2Krembil Research Institute, Toronto, Ontario M5T 0S8, Canada
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Philip Suetterlin
1Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom
3Craniofacial Development and Stem Cell Biology, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom
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Robert Hindges
1Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom
4MRC Centre for Neurodevelopmental Disorders, King's College London, London SE1 1UL, United Kingdom
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Uwe Drescher
1Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom
4MRC Centre for Neurodevelopmental Disorders, King's College London, London SE1 1UL, United Kingdom
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Abstract

Interstitial axon branching is an essential step during the establishment of neuronal connectivity. However, the exact mechanisms on how the number and position of branches are determined are still not fully understood. Here, we investigated the role of Arl8B, an adaptor molecule between lysosomes and kinesins. In chick retinal ganglion cells (RGCs), downregulation of Arl8B reduces axon branch density and shifts their location more proximally, while Arl8B overexpression leads to increased density and more distal positions of branches. These alterations correlate with changes in the location and density of lysosomes and autophagosomes along the axon shaft. Diminishing autophagy directly by knock-down of atg7, a key autophagy gene, reduces branch density, while induction of autophagy by rapamycin increases axon branching, indicating that autophagy plays a prominent role in axon branch formation. In vivo, local inactivation of autophagy in the retina using a mouse conditional knock-out approach disturbs retino-collicular map formation which is dependent on the formation of interstitial axon branches. These data suggest that Arl8B plays a principal role in the positioning of axon branches by spatially controlling autophagy, thus directly controlling formation of neural connectivity in the brain.

SIGNIFICANCE STATEMENT The formation of interstitial axonal branches plays a prominent role in numerous places of the developing brain during neural circuit establishment. We show here that the GTPase Arl8B controls density and location of interstitial axon branches, and at the same time controls also density and location of the autophagy machinery. Upregulation or downregulation of autophagy in vitro promotes or inhibits axon branching. Local disruption of autophagy in vivo disturbs retino-collicular mapping. Our data suggest that Arl8B controls axon branching by controlling locally autophagy. This work is one of the first reports showing a role of autophagy during early neural circuit development and suggests that autophagy in general plays a much more prominent role during brain development than previously anticipated.

  • autophagy
  • axon branching
  • lysosomes
  • neural circuit development
  • retinotectal projection
  • vesicle trafficking

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The Journal of Neuroscience: 40 (42)
Journal of Neuroscience
Vol. 40, Issue 42
14 Oct 2020
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The GTPase Arl8B Plays a Principle Role in the Positioning of Interstitial Axon Branches by Spatially Controlling Autophagosome and Lysosome Location
Gee Adnan, Aine Rubikaite, Moqadisa Khan, Michael Reber, Philip Suetterlin, Robert Hindges, Uwe Drescher
Journal of Neuroscience 14 October 2020, 40 (42) 8103-8118; DOI: 10.1523/JNEUROSCI.1759-19.2020

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The GTPase Arl8B Plays a Principle Role in the Positioning of Interstitial Axon Branches by Spatially Controlling Autophagosome and Lysosome Location
Gee Adnan, Aine Rubikaite, Moqadisa Khan, Michael Reber, Philip Suetterlin, Robert Hindges, Uwe Drescher
Journal of Neuroscience 14 October 2020, 40 (42) 8103-8118; DOI: 10.1523/JNEUROSCI.1759-19.2020
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Keywords

  • autophagy
  • axon branching
  • lysosomes
  • neural circuit development
  • retinotectal projection
  • vesicle trafficking

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