Distinct Rho GTPase effectors inhibit axon outgrowth and promote axon elongation

M BISBAL; J WOJNACKI; G QUASSOLLO; N UNSAIN; GF MARTÍNEZ; A SZALAI; M BORDENAVE; O PERTZ; G GUNDERSEN; F BARTOLINI; FD STEFANI; AO CÁCERES

Santa Cruz

Congreso; IUBMB EMBO Workshop Emerging Concepts of the Neuronal Cytoskeleton. Santa Cruz, Chile; 2023

EMBO

RhoA’s crucial role in neuronal polarization, where its action restrains axon outgrowth, has beenthoroughly documented. We now report that RhoA not only inhibits but also stimulates axondevelopment depending on when and where exerts its action and identify mDia as the Rho effector ofthis novel stimulatory effect of RhoA. In cultured hippocampal neurons, FRET imaging revealed thatRhoA activity selectively localizes in growth cones of undifferentiated neurites, while in developingaxons it displays a biphasic pattern, being low in nascent axons and high in elongating ones. RhoA-Rhokinase (ROCK) signaling prevents axon initiation but has no effect on elongation, while formin inhibitionreduces axon extension without significantly altering initial outgrowth.Besides, RhoA-mDia promotesaxon elongation by stimulating growth cone microtubule stability and assembly, as opposed toRhoA-ROCK that restrains growth cone microtubule assembly and protrusion. Finally, we show thatsimilar mechanisms operate during axonal regeneration, with RhoA-ROCK slowing axon regrowth afteraxotomy and RhoA-mDia favoring extension of regenerated axons.