Targeting MicroRNA-144/451-AKT-GSK3β Axis Affects the Proliferation and Differentiation of Radial Glial Cells in the Mouse Hippocampal Dentate Gyrus

Abstract

It is well known that aging induces a progressive decline in the proliferation and neural differentiation of radial glial cells (RGCs) in the hippocampal dentate gyrus (DG). The function of miR-144/451 is to activate stress-regulated molecular gene expression switches for cell proliferation and differentiation. We found that the miR-144/451 expression in the hippocampus was significantly reduced in aged mice compared to adult mice. Furthermore, the proliferation and neural differentiation of RGCs in the mouse hippocampal DG was decreased by miR-144/451 knockout (miR-144/451 −/− ). Antioxidant agents, superoxide dismutases (SODs) and catalase, and the expression of melatonin's receptor in the hippocampus were decreased in the miR-144/451 −/− mice. In addition, the (protein kinase B) AKT/(glycogen synthase kinase 3β) GSK3β/ (catenin beta-1) β-catenin signaling pathway was weakly activated in the hippocampus of miR-144/451 −/− mice, which was related to brain neurogenesis. Melatonin treatment improved the expression of miR-144/451 and antioxidant enzymes and activated the AKT/GSK3β/β-catenin pathway in the hippocampus of miR-144/ 451 −/− mice. When the AKT pathway was inhibited by LY294002, the neurogenerative and antioxidant effects of melatonin were significantly limited in the hippocampus of miR-144/451 −/− mice. In brief, our results indicated that miR-144/451 plays crucial roles in the proliferation and neural differentiation of RGCs via the regulation of the antioxidant and AKT/GSK3β/β-catenin pathways.