Spermatogenesis involves two critical events: 1. The detachment of spermatogonial cell progenies from basal lamina and Sertoli cell anchoring sites upon commitment to meiosis. 2. The elimination of nonviable spermatogenic cell progenies to regulate the balanced differentiation of spermatogenic cells into sperm. These developmental events imply a continuous morphological reorganization of the seminiferous epithelium whose structural and molecular details are unknown. Our overall hypothesis is that these two events are interrelated and under control by three interactive signaling pathways: 1. The integrin beta1 subunit of the alpha3beta1/alpha6beta1 complex. 2. Members of the disintegrin protein family. 3. Caspase-3, an essential mediator in apoptosis. An analysis of the molecular events linking these pathways has never been attempted. One objective of this proposal is to understand how Sertoli cell geometry controls the anchorage and viability of spermatogonial cell progenies and the second is to determine how the oscillatory movements of spermatogonial cells gate the execution of induced cell death. Our overall hypothesis is that Sertoli cell stretching and contraction govern the differentiation of the spermatogonial cell progeny and its translocation into the adluminal compartment of the seminiferous epithelium. We plan to: 1. Test the hypothesis that Sertoli cell geometry and beta1 integrin regulate the anchorage of spermatogonial cells to Sertoli cell surfaces. 2. Test the hypothesis that selected disintegrins can either disrupt or stabilize spermatogonial-Sertoli cell adhesion. 3. Test the hypothesis that enhanced spermatogonial oscillatory cell movements following Fas ligand-induced apoptosis are a prelude to imminent cell death initiated by the fragmentation of actin and gelsolin activated by apoptosis caspase-3. The significance of the proposed studies is two-fold: 1. To our knowledge, this is the first attempt to link Sertoli cell geometrical changes to the life-and-death of the spermatogonial cell progeny. 2. In the long range, the discovery of ways to prevent and modulate spermatogonial cell death may have significant therapeutic and anticonceptive potentials in humans.
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