TY - JOUR
T1 - The GADD45G/p38 MAPK/CDC25B signaling pathway enhances neurite outgrowth by promoting microtubule polymerization
AU - Kase, Yoshitaka
AU - Sato, Tsukika
AU - Okano, Yuji
AU - Okano, Hideyuki
N1 - Funding Information:
We thank Professor Shinya Yamanaka at the Center for iPS Cell Research and Application (CiRA), Kyoto University, for providing us with the 201B7 and 414C2 human iPSC lines. We thank M. Akizawa for her assistance with this work. We are grateful to Dr. Hiroyuki Kamiguchi (RIKEN Center for Brain Science) for critical reading of the manuscript. This work was supported by “Strategic Exploitation of Neuro-Genetics for Emergence of the Mind” supported by Funding Program for World-leading Innovative R&D on Science and Technology (FIRST) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), funding from the Japan Agency for Medical Research and Development (AMED) (grant number JP20bm0204001) (to H.O.), the General Insurance Association of Japan (to Y.K.), the Takeda Science Foundation (to Y.K.), and JSPS KAKENHI Grant Number 19K18438(to Y.K.). Finally, we would like to express our sincere gratitude to Prof. Takashi Gojobori and Mariko Hasegawa, Project Advisors of the FIRST program, for their invaluable advice on human-specific genes including hCONDEL and their roles. We would like to express our deepest gratitude to Professors. Takashi Gojobori and Mariko Hasegawa, Project Advisors of the FIRST program, for their invaluable advice on human-specific genes including hCONDEL and their roles. Y.K. obtained the funding, designed and performed the experiments, analyzed all results, and wrote the paper. T.S. and Y.O. performed the experiments and edited the paper. Y.O. analyzed the RNA-seq data. H.O. obtained the funding, edited the paper, and supervised this project. All authors approved the final manuscript. H.O. is a compensated scientific consultant for San Bio Co. Ltd.; RMiC; and K Pharma, Inc. The other authors declare no competing interests. We have a patent pending in Japan related to this work. We worked to ensure diversity in experimental samples through the selection of the cell lines. We worked to ensure diversity in experimental samples through the selection of the genomic datasets.
Funding Information:
This work was supported by “Strategic Exploitation of Neuro-Genetics for Emergence of the Mind” supported by Funding Program for World-leading Innovative R&D on Science and Technology (FIRST) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), funding from the Japan Agency for Medical Research and Development (AMED) (grant number JP20bm0204001 ) (to H.O.), the General Insurance Association of Japan (to Y.K.), the Takeda Science Foundation (to Y.K.), and JSPS KAKENHI Grant Number 19K18438 (to Y.K.).
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/4/15
Y1 - 2022/4/15
N2 - 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.
AB - 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.
KW - Biological sciences
KW - Cell biology
KW - Cellular neuroscience
KW - Neuroscience
UR - http://www.scopus.com/inward/record.url?scp=85128279291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85128279291&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2022.104089
DO - 10.1016/j.isci.2022.104089
M3 - Article
AN - SCOPUS:85128279291
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 4
M1 - 104089
ER -