RhoA drives actin compaction to restrict axon regeneration and astrocyte reactivity after CNS injury.

Autor:	Stern S; Laboratory of Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127 Bonn, Germany., Hilton BJ; Laboratory of Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127 Bonn, Germany., Burnside ER; Laboratory of Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127 Bonn, Germany., Dupraz S; Laboratory of Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127 Bonn, Germany., Handley EE; Laboratory of Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127 Bonn, Germany., Gonyer JM; Laboratory of Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127 Bonn, Germany., Brakebusch C; Biotech Research and Innovation Centre, Biomedical Institute, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark., Bradke F; Laboratory of Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127 Bonn, Germany. Electronic address: frank.bradke@dzne.de.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2021 Nov 03; Vol. 109 (21), pp. 3436-3455.e9. Date of Electronic Publication: 2021 Sep 10.
DOI:	10.1016/j.neuron.2021.08.014
Abstrakt:	An inhibitory extracellular milieu and neuron-intrinsic processes prevent axons from regenerating in the adult central nervous system (CNS). Here we show how the two aspects are interwoven. Genetic loss-of-function experiments determine that the small GTPase RhoA relays extracellular inhibitory signals to the cytoskeleton by adapting mechanisms set in place during neuronal polarization. In response to extracellular inhibitors, neuronal RhoA restricts axon regeneration by activating myosin II to compact actin and, thereby, restrain microtubule protrusion. However, astrocytic RhoA restricts injury-induced astrogliosis through myosin II independent of microtubules by activating Yes-activated protein (YAP) signaling. Cell-type-specific deletion in spinal-cord-injured mice shows that neuronal RhoA activation prevents axon regeneration, whereas astrocytic RhoA is beneficial for regenerating axons. These data demonstrate how extracellular inhibitors regulate axon regeneration, shed light on the capacity of reactive astrocytes to be growth inhibitory after CNS injury, and reveal cell-specific RhoA targeting as a promising therapeutic avenue. Competing Interests: Declaration of interests H. Witte, A. Ertürk, F. Hellal, and F.B. filed a patent on the use of microtubule-stabilizing compounds for the treatment of lesions of CNS axons (European Patent 1858498, European patent application EP 11 00 9155.0, U.S. patent application 11/908,118). (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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