Purinergic signaling networks in the testis – insight into the role(s) of peritubular cells

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The testis produces sperm and testosterone. Spermatogenesis takes place in the seminiferous tubules and testosterone is produced by interstitial Leydig cells. Spermatogenesis ranks among the most complex, yet least understood developmental processes in the body. Mechanistic information on the physiological machinery that orchestrates these cell transformation events and on intratesticular sperm transport, is sparse. Likewise, Leydig cell homeostasis is not well understood. The long-term goal of our joint research efforts is to gain detailed mechanistic insights into the roles of testicular signaling in both health and disease. We focus on testicular peritubular cells (TPCs). Strategically located at the interface of the seminiferous tubules and the interstitial compartment, TPCs emerge as crucial contributors to the functions of either unit. They contribute to the spermatogonial stem cell niche and testicular immune surveillance, however, the complex roles that TPCs play in testicular physiology, remain poorly defined. During the previous funding period, we showed that purinergic signals target TPCs and mediate distinct functions. While extracellular ATP causes coordinated contractions that provide the propulsive force for sperm transport, ATP metabolites (especially adenosine) serve pro-inflammatory functions in testis and TPCs. Pilot studies indicate that adenosine may further act as a molecule involved in Leydig cell homeostasis. These key findings highlight the two logical next steps for our collaborative endeavor: First, we need to understand the mechanistic basis of purine-dependent TPC contractions, both on the single cell and the TPC network level. Second, we must broaden our analytic scope to include ATP metabolites and consider their roles not only in sperm transport, but also in testis immunology/cellular homeostasis. Here, we propose a complementary joint effort to elucidate testicular purinergic signaling. We will employ the established repertoire of tools and extend it, in order to address these topics in human and mouse TPC cultures, organotypic testis cultures, mouse in vivo models, benefitting from a novel intravital imaging platform. We believe that these studies will generate a wealth of novel information that may bear potential importance for development of male contraceptives (interference with sperm transport), as well as for diagnosis and treatment of idiopathic male infertility or hypogonadism, respectively (interference with inflammation/ Leydig cell homeostasis). Based on our collaborative track record and synergistic sets of methods, we are ideally suited to tackle the ambitious goals outlined in this proposal.