Regulation of RhoA by STAT3 coordinates glial scar formation

Francois Renault-Mihara, Masahiko Mukaino, Munehisa Shinozaki, Hiromi Kumamaru, Satoshi Kawase, Matthieu Baudoux, Toshiki Ishibashi, Soya Kawabata, Yuichiro Nishiyama, Keiko Sugai, Kaori Yasutake, Seiji Okada, Masaya Nakamura, Hideyuki Okano

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Abstract

Understanding how the transcription factor signal transducer and activator of transcription-3 (STAT3) controls glial scar formation may have important clinical implications. We show that astrocytic STAT3 is associated with greater amounts of secreted MMP2, a crucial protease in scar formation. Moreover, we report that STAT3 inhibits the small GTPase RhoA and thereby controls actomyosin tonus, adhesion turnover, and migration of reactive astrocytes, as well as corralling of leukocytes in vitro. The inhibition of RhoA by STAT3 involves ezrin, the phosphorylation of which is reduced in STAT3-CKO astrocytes. Reduction of phosphatase and tensin homologue (PTEN) levels in STAT3-CKO rescues reactive astrocytes dynamics in vitro. By specific targeting of lesion-proximal, reactive astrocytes in Nestin-Cre mice, we show that reduction of PTEN rescues glial scar formation in Nestin-Stat3+/- mice. These findings reveal novel intracellular signaling mechanisms underlying the contribution of reactive astrocyte dynamics to glial scar formation.

Original languageEnglish
Pages (from-to)2533-2550
Number of pages18
JournalJournal of Cell Biology
Volume216
Issue number8
DOIs
Publication statusPublished - Jan 1 2017

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All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Renault-Mihara, F., Mukaino, M., Shinozaki, M., Kumamaru, H., Kawase, S., Baudoux, M., ... Okano, H. (2017). Regulation of RhoA by STAT3 coordinates glial scar formation. Journal of Cell Biology, 216(8), 2533-2550. https://doi.org/10.1083/jcb.201610102