Slit-Dependent Endocytic Trafficking of the Robo Receptor Is Required for Son of Sevenless Recruitment and Midline Axon Repulsion

PLoS Genetics
Rebecca K Chance, Greg J Bashaw

Abstract

Understanding how axon guidance receptors are activated by their extracellular ligands to regulate growth cone motility is critical to learning how proper wiring is established during development. Roundabout (Robo) is one such guidance receptor that mediates repulsion from its ligand Slit in both invertebrates and vertebrates. Here we show that endocytic trafficking of the Robo receptor in response to Slit-binding is necessary for its repulsive signaling output. Dose-dependent genetic interactions and in vitro Robo activation assays support a role for Clathrin-dependent endocytosis, and entry into both the early and late endosomes as positive regulators of Slit-Robo signaling. We identify two conserved motifs in Robo's cytoplasmic domain that are required for its Clathrin-dependent endocytosis and activation in vitro; gain of function and genetic rescue experiments provide strong evidence that these trafficking events are required for Robo repulsive guidance activity in vivo. Our data support a model in which Robo's ligand-dependent internalization from the cell surface to the late endosome is essential for receptor activation and proper repulsive guidance at the midline by allowing recruitment of the downstream effector Son of...Continue Reading

References

Oct 24, 1995·Proceedings of the National Academy of Sciences of the United States of America·G LiP D Stahl
Aug 1, 1993·The Journal of Cell Biology·A M van der BliekS L Schmid
Mar 21, 1997·Cell·M González-Gaitán, H Jäckle
Mar 9, 1999·Neuron·L M LanierF B Gertler
Nov 13, 1999·Nature Cell Biology·S ChristoforidisM Zerial
Aug 26, 2000·Science·M HattoriJ G Flanagan
Jan 10, 2002·Neuron·Kristin L WhitfordAnirvan Ghosh
Jan 24, 2002·Neuron·Lara D Hutson, Chi Bin Chien
Aug 31, 2002·Cell·Krystyna KelemanBarry J Dickson
Sep 16, 2003·Nature Cell Biology·Daniel J MarstonCatherine D Nobes
Sep 16, 2003·Journal of Neurobiology·Anita HsounaMark F A VanBerkum
Oct 1, 2003·The Journal of Cell Biology·Dolora WiscoBettina Winckler
Jun 23, 2004·Molecular and Cellular Neurosciences·Zhe LiuVasi Sundaresan
Jan 20, 2005·Nature Neuroscience·Krystyna KelemanBarry J Dickson
Mar 10, 2005·Proceedings of the National Academy of Sciences of the United States of America·Hailan HuGreg J Bashaw
Apr 26, 2005·Neuron·Christopher W CowanMichael E Greenberg
Mar 24, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Joseph L BartoeLindsay Hinck
Apr 12, 2006·The Journal of Cell Biology·Elaine S Seto, Hugo J Bellen
Jun 3, 2006·Developmental Cell·Eric MaciaTomas Kirchhausen
Jun 22, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Le Ma, Marc Tessier-Lavigne
Feb 14, 2008·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·A AnithaNorio Mori
Feb 27, 2008·The Journal of Cell Biology·Thomas VaccariDavid Bilder
Mar 25, 2008·The Journal of Biological Chemistry·Noémi FukuharaErhard Hohenester
Aug 21, 2008·The Journal of Biological Chemistry·Kai-Ti LinIryna M Ethell

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Citations

Dec 26, 2015·Biology·Mirka HomrichSimone Diestel
Sep 1, 2016·Development·Heike Blockus, Alain Chédotal
Jan 25, 2019·Development·Mariko Kinoshita-KawadaJane Y Wu
Mar 17, 2020·Investigative Ophthalmology & Visual Science·Tatyana AppelbaumGustavo D Aguirre
May 30, 2019·Nature Communications·Gael GenetAnne Eichmann
Aug 20, 2016·Neural Development·Marie C ReichertTimothy A Evans
Dec 9, 2017·G3 : Genes - Genomes - Genetics·Haley E BrownTimothy A Evans
Sep 14, 2019·Neural Development·J D ComerJ A Kaltschmidt
Aug 21, 2020·Developmental Biology·Madhavi Gorla, Greg J Bashaw

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