REV-ERB Agonist SR9009 Regulates the Proliferation and Neurite Outgrowth/Suppression of Cultured Rat Adult Hippocampal Neural Stem/Progenitor Cells in a Concentration-Dependent Manner.

REV-ERBs are heme-binding nuclear receptors that regulate the circadian rhythm and play important roles in the regulation of proliferation and the neuronal differentiation process in neuronal stem/progenitor cells in the adult brain. However, the effects of REV-ERB activation in the adult brain remain unclear. In this study, SR9009, a synthetic REV-ERB agonist that produces anxiolytic effects in mice, was used to treat undifferentiated and neuronally differentiated cultured rat adult hippocampal neural stem/progenitor cells (AHPs). The expression of Rev-erbβ was upregulated during neurogenesis in cultured rat AHPs, and Rev-erbβ knockdown analysis indicated that REV-ERBβ regulates the proliferation and neurite outgrowth of cultured rat AHPs. The application of a low concentration (0.1 µM) of the REV-ERB agonist SR9009 enhanced neurite outgrowth during neurogenesis in cultured rat AHPs, whereas the addition of a high concentration (2.5 µM) of SR9009 suppressed neurite outgrowth. Further examination of the SR9009 regulatory mechanism showed that the expressions of downstream target genes of REV-ERBβ, including Ccna2 and Sez6, were modulated by SR9009. The results of this study indicated that REV-ERBβ activity in cultured rat AHPs was regulated by SR9009 in a concentration-dependent manner. Furthermore, SR9009 inhibited the growth of cultured rat AHPs through various pathways, which may provide insight into the multifunctional mechanisms of action associated with SR9009. The findings of this study may provide an improved understanding of proliferation and neuronal maturation mechanisms in cultured rat AHPs through SR9009-regulated REV-ERBβ signaling pathways.