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

• DOI: 10.1016/j.neuron.2021.08.014
• Publication Date: 2021-09-10T14:28:51Z
• Authors: Sina Stern; Brett J. Hilton; Emily R. Burnside; Sebastian Dupraz; Emily E. Handley; Jessica M. Gonyer; Cord Brakebusch; Frank Bradke
• Keywords: Central Nervous System; 0301 basic medicine; pathology [Central Nervous System Diseases]; metabolism [Actins]; metabolism [Axons]; F-actin density; Mice; 03 medical and health sciences; metabolism [Central Nervous System Diseases]; myosin II; Central Nervous System Diseases; Animals; ddc:610; metabolism [Astrocytes]; axon regeneration; RhoA; Actins; Axons; Nerve Regeneration; physiology [Nerve Regeneration]; astrocyte reactivity; Astrocytes; metabolism [Central Nervous System]; pathology [Central Nervous System]; metabolism [rhoA GTP-Binding Protein]; rhoA GTP-Binding Protein; microtubule protrusion; YAP signaling

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.