CONTROL OF SERTOLI CELL PROLIFERATION

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A unique system has been developed for studying the factors which control the establishment of the adult number of Sertoli cells and the growth and sperm production of the testis. With this method, testis size and sperm production in adult rats can be increased 80% and 140%, respectively, by a short neonatal treatment with the reversible goitrogen 6-propyl-2-thiouracil (PTU). Furthermore, Sertoli cell numbers are increased by 170% in PTU-treated rats. The mechanisms by which PTU treatment increases testis growth and sperm production are unknown, but increased Sertoli cells proliferation appears to be the critical event in the development of this effect. The studies in this proposal will use both in vitro and in vivo approaches to determine the mechanism by which PTU treatment increases Sertoli cell numbers, and will test two basic hypotheses. First, that the lack of thyroid hormones in PTU-treated rats delays the maturation of Sertoli cells, allowing them to remain in a juvenile, proliferative stage longer during early postnatal development. Second, that another factor(s) (e.g., increased TSH and increased Sertoli cell responsiveness to FSH) stimulates Sertoli cell mitosis during this extended postnatal proliferative period, resulting in the increased adult Sertoli cell numbers and secondarily, the observed increases in testis weight and sperm production. The results of these studies should specifically increase our understanding of the role of thyroid hormones in Sertoli cell proliferation and further our knowledge of the factors which regulate early Sertoli cell proliferation and the establishment of the ultimate adult numbers of these cells. This study will determine: 1) Whether Sertoli cell proliferation is increased in magnitude and/or prolonged by PTU treatment; 2) if TSH can be mitogenic for Sertoli cells from treated and/or control rats in vitro; 3) whether PTU treatment increases the FSH responsiveness of Sertoli cells from treated rats; 4) if PTU treatment alters the age-related decrease in mitogenic responsiveness that normally occurs during the neonatal period; 5) whether thyroid hormones control the age-related decrease in mitogenic responsiveness of neonatal Sertoli cells; 6) possible differences in FSH receptor expression in control and treated Sertoli cells; 7) possible differences in thyroid hormone receptor expression in control and treated Sertoli cells; 8) the importance of Sertoli cell-germ cell interactions for the increased Sertoli cell proliferation seen in PTU-treated rats.