Evidence of the activation of unfolded protein response in granulosa and cumulus cells during follicular growth and maturation.

The objective of the present study is to investigate whether unfolded protein response (UPR), activated by endoplasmic reticulum (ER) stress, in granulosa cells (GC) and cumulus cells (CC) is involved in the process of follicular growth and maturation. First, to examine the presence of UPR in growing follicles, the expression of spliced form of X-box-binding protein 1 (XBP1(S)) and heat shock 70 kDa protein 5 (HSPA5) mRNA, typical UPR genes, in mice ovaries were examined by in situ hybridization. GC of later stage than large secondary follicles expressed both XBP1(S) and HSPA5 mRNA, which was accompanied with the activation of ER stress sensor proteins, inositol-requiring enzyme 1 (IRE1) and double-stranded RNA-activated protein kinase-like ER kinase (PERK), confirmed by immunohistochemistry. Next, to examine the association between the fertilization capacity of oocytes and the expression levels of UPR genes in surrounding CC, human CC were collected from patients undergoing ICSI. The expression levels of XBP1(S) mRNA, quantified by RT-PCR, in CC enclosing human oocytes achieving fertilization were two-fold higher, than those in CC enclosing oocytes without fertilization capacity. In conclusion, UPR is activated during follicular growth and suggested to be involved in the process of follicular growth and maturation.