Up-regulation of CD95 (Apo-1/Fas) is associated with spermatocyte apoptosis during the first round of spermatogenesis in the rat

Abstract

Apoptosis plays a major role in controlling both the rate of sperm production and chromosomal abnormalities in adult male testes. However, little is known on the mechanisms controlling induction and execution of apoptosis under physiological conditions. In this work we have uncovered a major role for the cell death receptor Fas in both the extrinsic and intrinsic pathways in normal germ cell apoptosis. We show here that Fas levels increased significantly in a group of germ cell in 25 d old rats, which were identified as spermatocytes and only a few spermatogonia. In addition, we show that isolated spermatocytes expressing high levels of Fas display activation of caspase-8, -9, -3, -6 and -2, as well as increased levels of intracellular calcium and decreased pH, which coincides with stabilization of p53, and transcriptional activation of PUMA and Fas. Therefore, our data strongly suggests that transcriptional up regulation of Fas could predispose a group of spermatocytes to Fas ligand triggering apoptosis by the extrinsic and intrinsic pathway.

TACE/ADAM17 is involved in germ cell apoptosis during rat spermatogenesis

“…We have shown that they express several apoptosis marker which strongly suggest that they are indeed in the process (Lizama et al 2007, Vergara et al 2010. Whether or not all apoptotic spermatogenic cells are FAS positive remains controversial, and it is possible that more than one cell death pathway could take place in germ cells.…”

“…We have previously shown that germ cell apoptosis during the first wave of spermatogenesis is associated with an upregulation of FAS, a death receptor involved in the extrinsic pathway of apoptosis (Lizama et al 2007). We have shown that they express several apoptosis marker which strongly suggest that they are indeed in the process (Lizama et al 2007, Vergara et al 2010.…”

“…Recently, it has been shown that ADAM10 regulates surface expression of FAS ligand (FASL) by inducing the shedding of its extracellular domain (Schulte et al 2007). We have shown that activation of the FAS receptor and the extrinsic pathway of apoptosis are relevant in naturally occurring apoptosis in 25-dayold rat testes (Lizama et al 2007). It therefore seems possible that ADAM10 inhibition increases the half-life of FASL at the Sertoli cell surface, resulting in a juxtacrine signal that elicits apoptosis in germ cells.…”

“…It has been shown that this massive wave of apoptosis peaks at 25 days after birth in the rat, affecting mainly germ cells in meiosis (pachytene spermatocytes). These cells show caspase-8, -9, -3, -6, and -2 activation, along with an upregulation of FAS receptors and the transcription factor p53 (Lizama et al 2007). However, the mechanisms inducing germ cell apoptosis are still unknown.…”

“…In the testis, an inactivating point mutation at the intracellular domain of KIT blocking the binding of phosphoinositide-3-phosphate kinase induces germ cell apoptosis and leads to infertility (Blume-Jensen et al 2000, Kissel et al 2000. In addition, genetic evidence from the mouse testis suggests that inactivation of KIT signaling is linked to apoptosis mediated by the expression of FAS, a type I transmembrane receptor belonging to the tumor necrosis factor (TNF)/nerve growth factor receptor family (Sakata et al 2003, Lizama et al 2007. In humans, associations between polymorphisms in the KIT gene and idiopathic infertility have also been found (Galan et al 2006).…”