Mesentery AjFGF4–AjFGFR2–ERK pathway modulates intestinal regeneration via targeting cell cycle in echinoderms

The purpose of the study aims to understand the regeneration process and its cytology mechanism in economic echinoderms.The intestine regeneration process of Apostichopus japonicus was investigated by immunohistochemistry and the cell proliferation was detected by immunofluorescence and flow cytometry. Fibroblast growth factor 4 of A. japonicus (AjFGF4) was screened by RNA-seq analysis and validated to regulate cell proliferation by siAjFGF4 and recombinant-AjFGF4 treatment. The binding and co-localization of AjFGF4 and AjFGFR2 were verified by Co-IP, GST-pull down, and immunofluorescence. Then, the AjFGF4-AjFGFR2-ERK-cell cycle axis was examined by western blot, immunofluorescence, and flow cytometry techniques.The mesentery was served as the epicenter of intestinal regeneration via activating cell proliferation and other cellular events. Mechanically, AjFGF4-mediated cell proliferation was dependent on the binding to its receptor AjFGFR2, and then triggered the conserved ERK-MAPK pathway but not JNK and p38 pathway. The activated ERK-MAPK subsequently mediated the expression of cell cycle regulatory proteins of CDK2, Cyclin A, and Cyclin B to promote cell proliferation.We provide the first functional evidence that AjFGF4-AjFGFR2-ERK-cell cycle axis mediated cell proliferation was the engine for mesentery-derived intestine regeneration in echinoderms.