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

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 in-dependent 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 astro-cytic 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.

Automated summary

Studies reveal that an inhibitory extracellular environment and neuron-intrinsic processes work together to prevent axon regeneration in the adult central nervous system. Genetic loss-of-function experiments show that the small GTPase RhoA relays extracellular inhibitory signals to the cytoskeleton. Neuronal RhoA restricts axon regeneration by activating myosin II, while astrocytic RhoA limits injury-induced astrogliosis through YAP signaling.