JNK-mediated Slit-Robo signaling facilitates epithelial wound repair by extruding dying cells

Chiaki Iida,Shizue Ohsawa,Tatsushi Igaki,Masatoshi Yamamoto,Ginés Morata,Kiichiro Taniguchi

doi:10.1038/s41598-019-56137-z

Chiaki Iida, Shizue Ohsawa + Show 4 more

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https://doi.org/10.1038/s41598-019-56137-z

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Multicellular organisms repair injured epithelium by evolutionarily conserved biological processes including activation of c-Jun N-terminal kinase (JNK) signaling. Here, we show in Drosophila imaginal epithelium that physical injury leads to the emergence of dying cells, which are extruded from the wounded tissue by JNK-induced Slit-Roundabout2 (Robo2) repulsive signaling. Reducing Slit-Robo2 signaling in the wounded tissue suppresses extrusion of dying cells and generates aberrant cells with highly upregulated growth factors Wingless (Wg) and Decapentaplegic (Dpp). The inappropriately elevated Wg and Dpp impairs wound repair, as halving one of these growth factor genes cancelled wound healing defects caused by Slit-Robo2 downregulation. Our data suggest that JNK-mediated Slit-Robo2 signaling contributes to epithelial wound repair by promoting extrusion of dying cells from the wounded tissue, which facilitates transient and appropriate induction of growth factors for proper wound healing.

Highlights

Multicellular organisms repair injured epithelium by evolutionarily conserved biological processes including activation of c-Jun N-terminal kinase (JNK) signaling
Genetic studies in Drosophila have shown that JNK signaling contributes to (1) actin remodeling to close wound edges[6,11], (2) reconstruction of lost tissue parts by activating growth promoters such as Yorkie (Yki, a YAP homolog)[12,13], Wg14, Dpp[15] and Myc[14], (3) facilitating cell reprograming via reducing the activity of polycomb-dependent silencing[16], and (4) induction of developmental delay by upregulating Drosophila insulin-like peptide 8 (Dilp8) to prolong the developmental period for recovery[17]
JNK-dependent cell extrusion is required for tumor-suppressive cell competition, the process in which oncogenic polarity-deficient cells such as scribble or discs large mutant cells are actively eliminated from epithelia when surrounded by wild-type cells[32,33,34,35,36,37]

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Introduction

Multicellular organisms repair injured epithelium by evolutionarily conserved biological processes including activation of c-Jun N-terminal kinase (JNK) signaling. We found in Drosophila epithelium that physical injury induces JNK activation, which promotes extrusion of dying cells via Slit-Robo[2] signaling.

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