Regulation Mechanism of Selective Atresia in Porcine Follicles: Regulation of Granulosa Cell Apoptosis during Atresia

Abstract

Abstract. More than 99% of follicles undergo a degenerative process known as "atresia", in mammalian ovaries, and only a few follicles ovulate during ovarian follicular development. We have investigated the molecular mechanism of selective follicular atresia in mammalian ovaries, and have reported that follicular selection dominantly depends on granulosa cell apoptosis. However, we have little knowledge of the molecular mechanisms that control apoptotic cell death in granulosa cells during follicle selection. To date, at least five cell death ligand-receptor systems [tumor necrosis factor (TNF)α and receptors, Fas (also called APO-1/CD95) ligand and receptors, TNF-related apoptosisinducing ligand (TRAIL; also called APO-2) and receptors, APO-3 ligand and receptors, and PFG-5 ligand and receptors] have been reported in granulosa cells of porcine ovaries. Some cell death ligand-receptor systems have "decoy" receptors, which act as inhibitors of cell death ligand-induced apoptosis in granulosa cells. Moreover, we showed that the porcine granulosa cell is a type II apoptotic cell, which has the mitochondrion-dependent apoptosis-signaling pathway. Briefly, the cell death receptor-mediated apoptosis signaling pathway in granulosa cells has been suggested to be as follows. (1) (7) Cytochrome c and ATP-dependent oligimerization of apoptotic protease-activating factor-1 (Apaf-1) allows recruitment of procaspase-9 into the apoptosome complex. Activation of procaspase-9 is mediated by means of a conformational change. (8) The activated caspase-9 cleaves downstream effector caspases (caspase-3). (9) Finally, apoptosis is induced. Recently, we found two intracellular inhibitor proteins [cellular FLICE-like inhibitory protein short form (cFLIPS) and long form (cFLIPL)], which were strongly expressed in granulosa cells, and they may act as anti-apoptotic/survival factors. Further in vivo and in vitro studies will elucidate the largely unknown molecular mechanisms, e. g.

Molecular Characteristics of Porcine Fas-associated Death Domain (FADD) and Procaspase-8

“…Overexpression of pFADD and pprocaspase-8 induced cell death in the HeLa-K cells. To date, we have investigated the follicular atretic mechanisms of follicular atresia in porcine ovaries [18][19][20][21][22][26][27][28][29][30][31] and have shown that g r a n u l o s a c e l l a p o p t o s i s i s a d o m i n a n t phenomenon in follicular atresia. Therefore, we examined whether overexpressed pFADD and pprocaspase-8 can induce apoptosis in the granulosa cells of human, murine, and porcine origin (KGN, KK1 and JC410, respectively).…”

“…We previously reported that death ligand/ receptor systems act as initiators of apoptosis in porcine granulosa cells [22,30,31] and showed that an intracellular inhibitory protein, cFLIP, inhibits apoptosis in granulosa cells by binding with the D E D o f F A D D a n d / o r p r o c a s p a s e -8 a n d interrupting the recruitment of procaspase-8 to FADD [29,30]. In the present study, we showed that both the molecular construction and function of apoptotic signaling factors are highly conserved.…”

“…Then, the apoptotic signal is transduced as described above. Recently, we found that cellular FLICE-like inhibitory protein (cFLIP) plays an anti-apoptotic role in the granulosa cells of healthy follicles in porcine ovaries [28][29][30][31]. Two splicing variants, a short form (cFLIP S ) and a long form (cFLIP L ), were identified.…”

Dihydrotestosterone influenced numbers of healthy follicles and follicular amounts of LH receptor mRNA during the follicular phase of the estrous cycle in gilts

“…Follicular health is regulated by interactions among multiple physiological processes that stimulate cell proliferation and survival or induce apoptotic cell death (Tsafriri & Braw 1984). Apoptosisinducing factors that have been identified in pig granulosa cells include tumor necrosis factor (TNF)-a, Fas ligand (TNF receptor superfamily member 6 or APO1), TNF related apoptosis-inducing ligand (also known as apoptosis-2, APO2), and APO3 (Manabe et al 2004). Whether androgens influenced the actions of one of these factors, other components of the complex intracellular apoptotic pathways, or apoptosis inhibitory mechanisms (survival factors), is not known.…”

Effect of RNA Interference of BID and BAX mRNAs on Apoptosis in Granulosa Cell-derived KGN Cells

“…58: [112][113][114][115][116] 2012) I n mammalian ovaries, more than 99% of follicles degenerate at various stages of follicular growth and development [1]. The degeneration is explained, at least in part, by the apoptosis of granulosa cells [2][3][4][5][6]. In porcine ovarian follicles in the early stages of atresia, characteristics typical of apoptosis are observed in scattered granulosa cells, but not in cumulus cells, oocytes or the cells of internal or external thecal layers [7].…”