The balance between ovarian folliculogenesis and follicular atresia is critical for female fertility and is strictly regulated by a complex network of neuroendocrine and intra-ovarian signals. Despite the numerous functions executed by granulosa cells (GCs) in ovarian physiology, the role of multifunctional proteins able to simultaneously coordinate/modulate several cellular pathways is unclear. Soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (α-SNAP) is a multifunctional protein that participates in SNARE-mediated membrane fusion events. In addition, it regulates cell-to-cell adhesion, AMPK signaling, autophagy and apoptosis in different cell types. In this study we examined the expression pattern of α-SNAP in ovarian tissue and the consequences of α-SNAP (M105I) mutation (hyh mutation) in folliculogenesis and female fertility. Our results showed that α-SNAP protein is highly expressed in GCs and its expression is modulated by gonadotropin stimuli. On the other hand, α-SNAP-mutant mice show a reduction in α-SNAP protein levels. Moreover, increased apoptosis of GCs and follicular atresia, reduced ovulation rate, and a dramatic decline in fertility is observed in α-SNAP-mutant females. In conclusion, α-SNAP plays a critical role in the balance between follicular development and atresia. Consequently, a reduction in its expression/function (M105I mutation) causes early depletion of ovarian follicles and female subfertility.
Bibliographical noteFunding Information:
The authors acknowledge the help of Jaime Romaní and Hernán Salinas in the maintenance of the animal facility. The authors also acknowledge the administrative support of Dr. Carlos Figueroa. MdP is thankful to CONICET, Argentina, for PhD fellowships. This work was supported by Chilean FONDECYT Regular grants 1141015 (LFB), 1161787 (FJR) and 1161252 (GAM), Chilean FONDECYT Postdoctoral grant 3130756 (ZDV), CISNe-UACh (LFB), Program for Cell Biology (PDBC)-UACh and DID-UACh (LFB), PLISSER (MdP), and Fogarty International Center R01TW007571 (MAM).
© 2017 The Author(s).