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VARIATION AND SELECTION IN AXON NAVIGATION THROUGH MICROTUBULE-DEPENDENT STEPWISE GROWTH CONE ADVANCE

Stephen G Turney, Indra Chandrasekar, Mostafa Ahmed, Robert M Rioux, George M Whitesides, Paul C Bridgman
doi: https://doi.org/10.1101/2020.01.29.925602
Stephen G Turney
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138
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Indra Chandrasekar
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110
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Mostafa Ahmed
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110
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Robert M Rioux
Department of Chemical Engineering, Pennsylvania State University, University Park, PA 16802Department of Chemistry, Pennsylvania State University, University Park, PA 16802
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George M Whitesides
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138.
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Paul C Bridgman
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110
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  • For correspondence: bridgmap@wustl.edu
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ABSTRACT

Myosin II (MII) activity is required for elongating mammalian sensory axons to change speed and direction in response to Nerve Growth Factor (NGF) and laminin-1 (LN). NGF signaling induces faster outgrowth on LN through regulation of actomyosin restraint of microtubule advance into the growth cone periphery. It remains unclear whether growth cone turning on LN works through the same mechanism and, if it does, how the mechanism produces directed advance. Using a novel method for substrate patterning, we tested how directed advance occurs on LN by creating a gap immediately in front of a growth cone advancing on a narrow LN path. The growth cone stopped until an actin-rich protrusion extended over the gap, adhered to LN, and became stabilized. Stepwise advance over the gap was triggered by microtubule +tip entry up to the adhesion site of the protrusion and was independent of traction force pulling. We found that the probability of microtubule entry is regulated at the level of the individual protrusion and is sensitive to the rate of microtubule polymerization and the rate of rearward actin flow as controlled by adhesion-cytoskeletal coupling and MII. We conclude that growth cone navigation is an iterative process of variation and selection. Growth cones extend leading edge actin-rich protrusions that adhere transiently (variation). Microtubule entry up to an adhesion site stabilizes a protrusion (selection) leading to engorgement, consolidation, protrusive activity distal to the adhesion site, and stepwise growth cone advance. The orientation of the protrusion determines the direction of advance.

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Posted January 31, 2020.
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VARIATION AND SELECTION IN AXON NAVIGATION THROUGH MICROTUBULE-DEPENDENT STEPWISE GROWTH CONE ADVANCE
Stephen G Turney, Indra Chandrasekar, Mostafa Ahmed, Robert M Rioux, George M Whitesides, Paul C Bridgman
bioRxiv 2020.01.29.925602; doi: https://doi.org/10.1101/2020.01.29.925602
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VARIATION AND SELECTION IN AXON NAVIGATION THROUGH MICROTUBULE-DEPENDENT STEPWISE GROWTH CONE ADVANCE
Stephen G Turney, Indra Chandrasekar, Mostafa Ahmed, Robert M Rioux, George M Whitesides, Paul C Bridgman
bioRxiv 2020.01.29.925602; doi: https://doi.org/10.1101/2020.01.29.925602

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