Androgens and NGF Mediate the Neurite-Outgrowth through Inactivation of RhoA

• Published in: Cells (Basel, Switzerland) Switzerland), 2023-01, Vol.12 (3), p.373
• Main Authors: Di Donato, Marzia, Bilancio, Antonio, Auricchio, Ferdinando, Castoria, Gabriella, Migliaccio, Antimo
• Format: Article
• Language: English
• Subjects: AKT protein; Alzheimer's disease; Androgen receptors; Androgens; Androgens - metabolism; Androgens - pharmacology; Animals; Axonogenesis; Brain damage; Cell culture; Cytoskeleton; Ectopic expression; Estrogens; Females; Guanosine triphosphatase; Hormones; Microscopy; Nerve growth factor; Nerve Growth Factor - metabolism; Nerve Growth Factor - pharmacology; Nervous system; Neurites - metabolism; Neurodegeneration; Neurological diseases; Neuromodulation; neuronal commitment; Neuronal Outgrowth; Neurons; PC12 Cells; Phenols; Pheochromocytoma cells; Phosphorylation; Physiological aspects; Protein-serine/threonine kinase; Rats; Receptors, Androgen - metabolism; Rho-associated kinase; RhoA protein; Signal transduction; small GTPases; Steroid hormones; Steroids; Testosterone; TrkA protein; TrkA receptors; Tubulin
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12030373

Steroid hormones and growth factors control neuritogenesis through their cognate receptors under physiological and pathological conditions. We have already shown that nerve growth factor and androgens induce neurite outgrowth of PC12 cells through a reciprocal crosstalk between the NGF receptor, TrkA and the androgen receptor. Here, we report that androgens or NGF induce neuritogenesis in PC12 cells through inactivation of RhoA. Ectopic expression of the dominant negative RhoA N19 promotes, indeed, the neurite-elongation of unchallenged and androgen- or NGF-challenged PC12 cells and the increase in the expression levels of βIII tubulin, a specific neuronal marker. Pharmacological inhibition of the Ser/Thr kinase ROCK, an RhoA effector, induces neuritogenesis in unchallenged PC12 cells, and potentiates the effect of androgens and NGF, confirming the role of RhoA/ROCK axis in the neuritogenesis induced by androgen and NGF, through the phosphorylation of Akt. These findings suggest that therapies based on new selective androgen receptor modulators and/or RhoA/ROCK inhibitors might exert beneficial effects in the treatment of neuro-disorders, neurological diseases and ageing-related processes.