Effects of TGF-betas and a specific antagonist on apoptosis of immature rat male germ cells in vitro |
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Authors: | L Konrad M M Keilani L Laible U Nottelmann R Hofmann |
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Institution: | (1) Department of Urology, Medical Faculty, 35033 Marburg, Germany;(2) Department of Urology, Baldingerstr, D-35033 Marburg, Germany |
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Abstract: | Massive apoptosis of pubertal male germ cells is important for the development of functional spermatogenesis in the adult
testis. Although the trigger(s) for male germ cell loss at puberty remain undefined, we have hypothesized that transforming
growth factor-betas (TGF-βs) play an active role. Here we demonstrate that the three mammalian TGF-β isoforms, TGF-β1, TGF-β2
and TGF-β3, induce distinct apoptosis of pubertal spermatogonia and spermatocytes in a dose-dependent manner. Induction of
male germ cell death by activation of caspase-3 was most pronounced with TGF-β2 compared to TGF-β1 and TGF-β3. Furthermore,
we found colocalization of activated caspase-3 with apoptotic protease-activating factor-1 (Apaf-1) in apoptotic germ cells,
thus indicating the importance of the intrinsic mitochondrial pathway in TGF-β-induced apoptosis. The specificity of the TGF-β
effects was proven by addition of recombinant latency-associated peptide against TGF-β1 (rLAP-TGF-β1) which completely abolished
TGF-β1-induced and TGF-β3-induced germ cell apoptosis. Although TGF-β2-triggered germ cell death also was significantly reduced
by rLAP-TGF-β1, inhibition was not maximal. Our results suggest that the three TGF-β isoforms induce apoptosis of pubertal
male germ cells via the mitochondrial pathway in vitro and are thus likely candidates involved in the excessive first wave of apoptosis of male germ cells during puberty.
Lutz Konrad and Marcel Munir Keilani contributed equally to this work. |
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Keywords: | antagonists apoptosis germ cells testis TGF-β 1-3 |
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