RhoA Controls Axon Extension Independent of Specification in the Developing Brain

TY - JOUR

T1 - RhoA Controls Axon Extension Independent of Specification in the Developing Brain

AU - Dupraz, Sebastian

AU - Hilton, Brett J

AU - Husch, Andreas

AU - Santos, Telma E

AU - Coles, Charlotte H

AU - Stern, Sina

AU - Brakebusch, Cord

AU - Bradke, Frank

N1 - Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.

PY - 2019/11/18

Y1 - 2019/11/18

N2 - The specification of an axon and its subsequent outgrowth are key steps during neuronal polarization, a prerequisite to wire the brain. The Rho-guanosine triphosphatase (GTPase) RhoA is believed to be a central player in these processes. However, its physiological role has remained undefined. Here, genetic loss- and gain-of-function experiments combined with time-lapse microscopy, cell culture, and in vivo analysis show that RhoA is not involved in axon specification but confines the initiation of neuronal polarization and axon outgrowth during development. Biochemical analysis and super-resolution microscopy together with molecular and pharmacological manipulations reveal that RhoA restrains axon growth by activating myosin-II-mediated actin arc formation in the growth cone to prevent microtubules from protruding toward the leading edge. Through this mechanism, RhoA regulates the duration of axon growth and pause phases, thus controlling the tightly timed extension of developing axons. Thereby, this work unravels physiologically relevant players coordinating actin-microtubule interactions during axon growth.

AB - The specification of an axon and its subsequent outgrowth are key steps during neuronal polarization, a prerequisite to wire the brain. The Rho-guanosine triphosphatase (GTPase) RhoA is believed to be a central player in these processes. However, its physiological role has remained undefined. Here, genetic loss- and gain-of-function experiments combined with time-lapse microscopy, cell culture, and in vivo analysis show that RhoA is not involved in axon specification but confines the initiation of neuronal polarization and axon outgrowth during development. Biochemical analysis and super-resolution microscopy together with molecular and pharmacological manipulations reveal that RhoA restrains axon growth by activating myosin-II-mediated actin arc formation in the growth cone to prevent microtubules from protruding toward the leading edge. Through this mechanism, RhoA regulates the duration of axon growth and pause phases, thus controlling the tightly timed extension of developing axons. Thereby, this work unravels physiologically relevant players coordinating actin-microtubule interactions during axon growth.

U2 - 10.1016/j.cub.2019.09.040

DO - 10.1016/j.cub.2019.09.040

M3 - Journal article

C2 - 31679934

SN - 0960-9822

VL - 29

SP - 3874

EP - 3886

JO - Current Biology

JF - Current Biology

IS - 22

ER -