The Photoperiod Regulates Granulosa Cell Apoptosis through the FSH-Nodal/ALK7 Signaling Pathway in Phodopus sungorus

SIMPLE SUMMARY: The photoperiod regulates the follicle development in the seasonal reproduction of animals through the HPO axis, which enables the offspring to be born in specific seasons to better adapt to the external environment. However, the specific mechanism remains unclear. Granulosa cells in the ovary are crucial for the follicle development and the maintenance of the ovarian function. This study focused on the structure of ovaries and the development state of the granulosa cells under different photoperiods, to determine the molecular mechanism of the photoperiod regulating follicle development in the seasonal reproduction of animals. We found that, under different photoperiods, the synergistic effect of hormones in the HPO axis ultimately affects the FSH secretion, participates in the regulation of the Nodal/ALK7 signaling pathway, and regulates the granulosa cell apoptosis, thus affecting the ovarian function, and ultimately, seasonal reproduction. These results suggest that partial molecular mechanisms of the seasonal reproduction and provide a theory basis to manipulate the animal reproduction. ABSTRACT: The photoperiod regulates the seasonal reproduction of mammals by affecting the follicle development, for which the granulosa cells provide nutrition. However, the underlying mechanism remains unclear. Here, Djungarian hamsters (Phodopus sungorus) were raised under different photoperiods to study the ovarian status and explore the potential mechanism of the follicle development mediated by the FSH-Nodal/ALK7 signaling pathway. Compared with the moderate daylight (MD) group, the short daylight (SD) group exhibited a significant decrease in the ovarian weight and increase in the atretic follicle number and granulosa cell apoptosis, whereas the long daylight (LD) group showed an increase in the ovarian weight, the growing follicle number, and the antral follicle number, but a decrease in the granulosa cell apoptosis. Based on these findings, the key genes of the Nodal/ALK7 signaling pathway controlling the granulosa cell apoptosis were studied using the quantitative real-time polymerase chain reaction and western blotting. In the SD group, the follicle-stimulating hormone (FSH) concentration significantly decreased and the Nodal/ALK7/Smad signaling pathways were activated, while the phosphatidylinositol 3-kinase (PIK3)/Akt signaling pathway was inhibited. The BAX expression was significantly increased, while the Bcl-xL expression was significantly decreased, leading to an increase in the caspase-3 activity, the granulosa cell apoptosis, and ovarian degeneration. However, in the LD group, the FSH concentration significantly increased, the Nodal/ALK7/Smad signaling pathway was inhibited, and the PIK3/Akt signaling pathway was activated. Taken together, our results indicate that the photoperiod can regulate the apoptosis of the granulosa cells by regulating the concentration of FSH, activating or inhibiting the Nodal/ALK7 signaling pathway, thereby affecting the ovarian function. Our research provides an important theoretical basis for understanding the photoperiod-regulated mechanisms of the mammalian seasonal reproduction.