Abstract
RhoA-GTPase (RhoA) is widely regarded as a key molecular switch to inhibit neurite outgrowth by rigidifying the actin cytoskeleton. However, during neurite outgrowth, whether and how microtubule dynamics are regulated by RhoA remains to be elucidated. Herein, CT04 and Y27632 were used to inactivate RhoA and its downstream effector Rho-associated coiled coil-forming kinase (ROCK), while the RhoAQ63L lentiviral vector was utilized to overexpress the constitutively activated RhoA in dorsal root ganglion (DRG) neurons or neuronal differentiated PC12 cells. The current data illustrate that the RhoA signaling pathway negatively modulates neurite outgrowth and elevates the expression of Glu-tubulin (a marker for a stabilized microtubule). Meanwhile, the microtubule-severing proteins spastin and p60-katanin were downregulated by the RhoA signaling pathway. When spastin and p60-katanin were knocked down, the effects of RhoA inhibition on neurite outgrowth were significantly reversed. Taken together, this study demonstrates that the RhoA pathway-mediated inhibition of neurite outgrowth is not only related to the modulation of microfilament dynamics but is also attributable to the regulation of the expression of spastin and p60-katanin and thus influences microtubule dynamics.
Highlights
Neurite outgrowth is a requisite process for the development and regeneration of the nervous system, through which connections between neurons and their targets can be built up [1,2]
In order to investigate the effect of RhoA on neurite outgrowth, the cultured dorsal root ganglion (DRG) neurons were treated with CT04 for 24 h
The results showed that CT04 treatment of DRG neurons exerts a statistically significant, positive neurite outgrowth effect
Summary
Neurite outgrowth is a requisite process for the development and regeneration of the nervous system, through which connections between neurons and their targets can be built up [1,2]. A wealth of evidence has demonstrated that cytoskeletal (actin microfilament and microtubules) dynamics play central roles in neurite outgrowth [1,3]. Many studies have suggested that the assembly of actin filaments in the growth cone is essential for axon guidance [4,5]. Microtubules are crucial for axon elongation, organelle transport, and growth cone motility. The mechanisms of actin filaments dependent on growth cone steering and axonal regeneration, via signaling cascades, are well documented [4,5]. The underlying molecular mechanism of neurite outgrowth through extracellular signals is far from fully understood
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