Arhgef1 negatively regulates neurite outgrowth through activation of RhoA signaling pathways.

Neurite outgrowth is essential for the establishment of functional neuronal connections during brain development. This study identifies that Arhgef1 is predominantly expressed in early neuronal developmental stages and negatively regulates neurite outgrowth. Knockdown of Arhgef1 in either Neuro-2a cells or primary cortical neurons leads to excess growth of neurites, whereas overexpression of Arhgef1 prominently restricts neurite formation. Arhgef1 strongly activates RhoA activity while concomitantly inhibits Rac1 and Cdc42 activities. Pharmacological blockade of RhoA activity restores normal neurite outgrowth in Arhgef1-overexpressed neurons. Importantly, Arhgef1 promotes F-actin polymerization in neurons, probably through inhibiting the activity of the actin-depolymerizing factor cofilin. Collectively, these findings reveal that Arhgef1 functions as a negative regulator of neurite outgrowth through regulating RhoA-cofilin pathway and actin dynamics.