The Regulation of Ovarian Granulosa Cell Death by Pro- and Anti-apoptotic Molecules

Abstract

Abstract. In the mammalian ovary, follicular development and atresia are closely regulated by cell death and survival-promoting factors, including hormones (gonadotropins) and intraovarian regulators (gonadal steroids, cytokines, and intracellular proteins). Several hundred thousand primordial follicles are present in the mammalian ovary; however, only a limited number of primordial follicles develop to the preovulatory stage and ovulate. The others, more than 99% of follicles, will be eliminated via a degenerative process known as "atresia". The endocrinological regulatory mechanisms involved in follicular development and atresia have been characterized to a large extent, but the precise temporal and molecular mechanisms involved in the regulation of these events have remained largely unknown. Recent studies suggest that the apoptosis of ovarian granulosa cells plays a major role in follicular atresia. In this review, we provide an overview of development and atresia of follicles, and apoptosis of granulosa cells in mammals. Key words: Anti-apoptotic factor, Apoptosis, Follicular atresia, Granulosa cell, Porcine ovary, Proapoptotic factor (J. Reprod. Dev. 52: [695][696][697][698][699][700][701][702][703][704][705] 2006) poptosis plays a significant role in almost all physiological functions in vertebrate and invertebrate species. It is a form of cell death essential for elimination of cells that are damaged, senescent, potentially harmful, or no longer useful [ 1 ] . T h e m a j o r f e a t u r e s o f a p o p t o s i s a r e internucleosomal DNA fragmentation, cell shrinkage, plasma membrane blebbing, and the formation of apoptotic bodies. Stimulation by death ligands or deprivation of key survivalpromoting growth factors is the main contributor to apoptosis, while stress inducers, including drugs, toxicants, oxidative stress, and radiation, are also known to cause apoptosis.Studies have revealed that apoptosis also plays a crucial role in maintaining the reproductive a p p a r a t u s . D u r i n g f o l l i c u l a r g r o w t h a n d development, more than 99% of follicles disappear, primarily due to apoptosis of granulosa cells [2][3][4][5] (Fig. 1). Both the biochemical and morphological characteristics of apoptosis have been observed in the granulosa cells of atretic follicles [6][7][8]. Apoptotic stimuli and intracellular signal transduction pathways involved in the apoptosis of granulosa cells remain to be determined, and investigators are studying potential triggers of apoptosis and how intracellular apoptotic signals are transmitted in granulosa cells.

Age-associated up-regulation of EGR1 promotes granulosa cell apoptosis during follicle atresia in mice through the NF-κB pathway

“…34 Previous studies have demonstrated that both pathways are involved in GCs apoptosis. 26,35 However, as shown in the present study, we found that GC apoptosis driven by EGR1 overexpression induced hallmarks of mitochondrial apoptosis (BCL2, CAS-PASE-9 and CASPASE-3). In contrast, EGR1 overexpression had no effect on the components of the death receptor pathway (CASPASE-8).…”

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.…”

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].…”