c-Flip expression and function in fetal mouse gonocytes.
Apoptosis is a key mechanism in spermatogenesis, and in testis, most gonocytes degenerate at fetal and postnatal ages to select a cell subset committed to become germ stem cells. The aim of the present study is to investigate mechanisms controlling the massive apoptosis of fetal gonocytes. We evaluated the expression and function of c-Flip, an apoptosis inhibitor known to interfere with the proapoptotic Fas-signaling pathway in a variety of cell types, but never investigated in fetal testis. Expression of c-Flip long isoform (c-FlipL) within fetal testis was localized in gonocytes at 16.5 and 18.5 days post coitum (dpc), both at the mRNA and protein level, while it was weakly expressed or undetectable at earlier stages. Moreover, Fas protein was found in fetal testes at 13.5, 16.5, and 18.5 dpc. Testes at 18.5 dpc, expressing high levels of c-FlipL, were resistant to Fas-induced apoptosis while they became highly sensitive when c-FlipL was inhibited by antisense c-Flip oligos. In addition, there was an inverse relation between gonocyte spontaneous apoptosis sensitivity and c-FlipL levels. Furthermore, caspase-10 activity was inversely related with c-FlipL expression, suggesting that caspase-10 might be a target of c-FlipL. These data represent the first evidence demonstrating c-Flip expression in fetal testes and its role in protecting gonocytes from Fas-dependent apoptosis.
Giampietri
Claudia
C
Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Histology and Medical Embryology, University of Rome La Sapienza, Rome, Italy. claudia.giampietri@uniroma1.it
Petrungaro
Simonetta
S
Klinger
Francesca G
FG
Coluccia
Pierpaolo
P
Paone
Alessio
A
Vivarelli
Elisabetta
E
Filippini
Antonio
A
De Cesaris
Paola
P
De Felici
Massimo
M
Ziparo
Elio
E
D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053455:Caspase 10; D020169:Caspases / Q000378:metabolism; D005333:Fetus / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D013737:Testis / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D019014:fas Receptor
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; C491899:Fas protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D053455:Caspase 10; D020169:Caspases