GADD45G, one of the genes containing the human-specific conserved deletion enhancer-sequence (hCONDEL), has contributed to the evolution of the human cerebrum, but its function in human neurons has not been established. Here, we show that the GADD45G/p38 MAPK/CDC25B signaling pathway promotes neurite outgrowth in human neurons by facilitating microtubule polymerization. This pathway ultimately promotes dephosphorylation of phosphorylated CRMP2 which in turn promotes microtubule assembly. We also found that GADD45G was highly expressed in developing human cerebral specimens. In addition, RK-682, which is the inhibitor of a phosphatase of p38 MAPK and was found in Streptomyces sp., was shown to promote microtubule polymerization and neurite outgrowth by enhancing p38 MAPK/CDC25B signaling. These in vitro and in vivo results indicate that GADD45G/p38 MAPK/CDC25B enhances neurite outgrowth in human neurons.
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