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  • Apoptose, Spermatogenèse, Spermatozoïdes
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Apoptose et spermatogenèse

Spermatogenesis and apoptosis

Andrologie volume 13, pages 209–216 (2003)Cite this article

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L’initiation de la spermatogenèse s’accompagne d’une vague d’apoptose qui limite l’efficience des premiers cycles spermatogénétiques chez la plupart des mammifères. Au delà des premiers cycles, le rendement théorique n’est jamais atteint traduisant l’existence d’une perte cellulaire. Parmi les cellules germinales, les spermatogonies sont des cibles privilégiées d’une apoptose physiologique. Ce processus est étroitement lié aux relations établies par les cellules germinales avec les cellules de Sertoli, le concept de régulation densité dépendante datant de la fin des années 80. La nécessaire synchronisation des étapes de la spermatogenèse exige que le cycle cellulaire progresse plutôt qu’il ne s’arrête, ce qui pourrait expliquer la plus grande sensibilité des cellules germinales à l’apoptose. Le prix à payer est que l’équilibre entre prolifération et mort cellulaire peut être facilement perturbé dans l’un ou l’autre sens.

Les premières approches réalisées pour comprendre les mécanismes en jeu dans l’apoptose des cellules germinales ont exploré sa dépendance hormonale (hormones gonadotropes, stéroïdes). Cependant, les situations observées ne permettaient pas d’établir de lien direct avec les voies de transduction et les mécanismes de régulation de l’apoptose au niveau testiculaire. Les étapes qui ont suivi concernent le démembrement des voies de transduction impliquées dans l’apoptose et leur régulation au cours de la spermatogenèse.

L’implication des gènes de la familleBcl-2 est reconnue même si l’expression de certains de ses membres reste controversée. Les données résultant de la surexpression de certains gènes (Bcl-2, Bcl-xl) et les données issues des inactivations de certains gènes(Bax) confirment le rôle exercé par ces gènes dans le contrôle de l’apoptose au niveau testiculaire tout en soulignant la stricte nécessité d’une régulation densité dépendante de la spermatogenèse. Plus récemment des profils d’expression de ces gènes ou protéines ont été décrits, avec des variations susceptibles d’expliquer certains résultats contradictoires de la littérature.

La place du système Fas/Fas ligand dans l’apoptose physiologique accompagnant les premiers cycles spermatogenétiques reste controversée alors que sa mise en jeu lors de certaines agressions chimio ou radio-thérapeutiques est admise. Cependant, l’inactivation du gène codant pour Fas ou son ligand ne génère pas d’infertilité ce qui limite son importance physiologique au niveau testiculaire.

L’identification et le démembrement du système TNF (Tumor Necrosis Factor) et de ses récepteurs ne fait que commencer. L’expression de certaines protéines impliquées dans cette voie ou reliées à cette voie a été confirmée au niveau testiculaire mais semble plutôt concerner des étapes postméiotiques de la spermatogénèse.

Parmi les oncogènes susceptibles de réguler ce phénomène, le coupleKit/Stem Cell Factor occupe une place singulière du fait de son expression au niveau testiculaire et de son rôle bien établi au cours du développement gonadique ainsi que dans la survie et la prolifération des spermatogonies différenciées. En utilisant un modèle transgénique de souris hétérozygote pour l’inactivation par transgenèse du gèneKit, nous avons pu montrer l’incapacité d’une seule copie du gèneKit à préserver une spermatogenèse et une fertilité normales chez la souris. En outre les résultats observés suggèrent l’intervention de ce gène à différentes phases de la spermatogenèse, selon des voies de transduction qui pourraient diverger.

Au total l’analyse des voies et mécanismes contrôlant l’apoptose au cours de la spermatogenèse sont des étapes clés pour la compréhension de certains troubles de la spermatogenèse comme de la genèse des tumeurs testiculaires à cellules germinales.

Abstract

Onset of spermatogenesis is associated with a wave of apoptosis, which limits its efficacy during the first cycles in most mammals. After the first cycles, the actual efficacy of spermatogenesis always remains below the theoretical yield. Among the germinal cells, spermatogonia are the main targets of physiological apoptosis. This physiological apoptosis partly depends on the relationships between germ cells and Sertoli cells. The impact of the Sertoli cell/germ cell number ratio on the efficacy of spermatogenesis is well accepted, the concept of density-dependent regulation in the seminiferous tubule was proposed in the early eighties. Since the steps of spermatogenesis require a continuous progression of the cell cycle rather than an arrest, germ cells might therefore be more sensitive to apoptosis. This may also lead to severe disturbances between proliferation and cell death.

The first experiments designed to elucidate the mechanisms of germ cell apoptosis were based on hormonal deprivation or cryptorchidism. However, the link between hormonal or cellular action and cell survival remained to be established. Analysis of signal transduction pathways involved in germ cell apoptosis and their regulation were the next steps.

The involvement of bcl-2 family genes has been confirmed, although the expression of some of its members remains more controversial. Data derived from overexpression of some genes (Bcl-2, Bcl-xl) or resulting from gene inactivation (Bax) at the testicular level have highlighted the role of these genes in the control of germ cell apoptosis and have also provided some evidence for the strict requirement for density-dependent regulation of spermatogenesis. More recently, variations in the pattern of expression of these genes or proteins helped to explain some of the discrepancies in the literature.

The place of the Fas/Fas ligand system during the first cycle of spermatogenesis remains a matter of debate, with controversies concerning the precise site of expression of this oncogene and its receptor. Conversely, its role in the testis after chemotoxic or radiotoxic treatments is well established. However, the normal fertility of animals with a spontaneous inactivation of Fas or Fas L genes does not support a physiological role of these factors during spermatogenesis.

While factors involved in TNF/TNF R1 (Tumor Necrosis Factor) are under study, some data have been reported concerning the role of TRAIL (TNFalpha Related Apoptosis Inducing Ligand) and its active or decoy receptors in the testis.

Among the oncogenes which may modulate the apoptotic process, Kit/Stem Cell Factor is particularly interesting, as Kit is expressed in some germ cells and Leydig cells, whereas SCF is expressed by Sertoli cells. Its impact during gonadal development and in the survival and proliferation of differentiated spermatogonia has been clearly established. Using a transgenic mice model, in which the Kit gene was inactivated by the insertion of a nls-lacZ sequence in its first exon, we showed that one single copy of the gene was unable to sustain physiological spermatogenesis and fertility in male mice. Our results also suggest that the Kit gene might be expressed at different steps of spermatogenesis, with different signal transduction pathways and biological actions.

Finally, analysis of the signal transduction pathways involved in testicular apoptosis and their mechanisms of control is one of the key steps to a better understanding of both impairment of spermatogenesis and the pathogenesis of certain germ cell tumours.

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Authors and Affiliations

  1. Biologie de la Reproduction, UMR «Physiologie de la Reproduction et des Comportements» Inra/Cnrs/Université de Tours, Chu Bretonneau, Faculté de Médecine, 37044, Tours cedex

    Dominique Royere, Fabrice Guerif, Véronique Laurent-Cadoret & Marie -Thérèse Hochereau de Reviers

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  1. Dominique Royere
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  2. Fabrice Guerif
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  3. Véronique Laurent-Cadoret
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Royere, D., Guerif, F., Laurent-Cadoret, V. et al. Apoptose et spermatogenèse. Androl. 13, 209–216 (2003). https://doi.org/10.1007/BF03034874

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Basic and Clinical Andrology

ISSN: 2051-4190