TY  - JOUR
AU  - Stern, Sina
AU  - Hilton, Brett Jason
AU  - Burnside, Emily
AU  - Dupraz, Sebastian
AU  - Handley, Emily
AU  - Gonyer, Jessica
AU  - Brakebusch, Cord
AU  - Bradke, Frank
TI  - RhoA drives actin compaction to restrict axon regeneration and astrocyte reactivity after CNS injury.
JO  - Neuron
VL  - 109
IS  - 21
SN  - 0896-6273
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2021-01386
SP  - 3436 - 3455.e9
PY  - 2021
AB  - 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.
KW  - Actins: metabolism
KW  - Animals
KW  - Astrocytes: metabolism
KW  - Axons: metabolism
KW  - Central Nervous System: metabolism
KW  - Central Nervous System: pathology
KW  - Central Nervous System Diseases: metabolism
KW  - Central Nervous System Diseases: pathology
KW  - Mice
KW  - Nerve Regeneration: physiology
KW  - rhoA GTP-Binding Protein: metabolism
KW  - F-actin density (Other)
KW  - RhoA (Other)
KW  - YAP signaling (Other)
KW  - astrocyte reactivity (Other)
KW  - axon regeneration (Other)
KW  - microtubule protrusion (Other)
KW  - myosin II (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34508667
DO  - DOI:10.1016/j.neuron.2021.08.014
UR  - https://pub.dzne.de/record/162729
ER  -