Interactions between developing male gametes and adjacent Sertoli cells are essential for spermatogenesis. Sertoli cells express genes encoding cell adhesion molecules, growth factors, transport proteins, proteases and protease inhibitors required by male germ cells. Germ cells regulate expression by Sertoli cells of many of these genes. Consequently, expression of these genes changes as the adjacent germ progress through the stages of the cycle of the seminiferous epithelium. This application examines the regulation and biological consequences of stage-specific gene expression by Sertoli cells from the perspective of the cathepsin L gene. Transcription of this gene increases more than 10-fold as adjacent germ cells progress from stage I to stages VI and VII and then decreases to undetectable levels when germ cells reach stage X. This cycle of gene expression is a response to germ cells which causes sequential repression, stimulation and re-repression of transcription of the cathepsin L gene. We have identified 2 domains in the cathepsin L gene that potentially respond to these signals: [1] An upstream repressor domain responds to inhibitory signals from germ cells [2] A 120 bp activation domain is stimulated upon the culmination of testis maturation, which is characterized by the completion of the first wave of spermatogenesis. These domains are functional in vivo; a 3kb fragment of the cathepsin L gene confers both Sertoli cell-specific and stagespecific expression of a reporter in transgenic mice. This application also proposes to examine the function of cathepsin L in the seminiferous epithelium. Those experiments are prompted by our observation that mice which express catalytically inactive cathepsin L exhibit an increased incidence of seminiferous tubule atrophy and produce 30% fewer spermatids in nonatrophic tubules than are produced by control mice. Building on all of these data, this proposal asks four questions which are our specific aims: 1 What are the specific cis-acting elements in the activation domain and what are their functions? 2. What is the identity of the transcription factors that bind to the maturation domain? Is their expression stage-specific amd maturation-dependent? 3. What cis-acting elements and which spermatogenic cells repress cathepsin L promoter activity in Sertoli cells? 4. What is the function of cathepsin L in the seminiferous epithelium? ? ? ?

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZRG1-REN (01))
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Rankin, Tracy L
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Johns Hopkins University
Schools of Public Health
United States
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Visone, Thomas; Charron, Martin; Wright, William W (2009) Activation and repression domains within the promoter of the rat cathepsin L gene orchestrate sertoli cell-specific and stage-specific gene transcription in transgenic mice. Biol Reprod 81:571-9
Johnston, Daniel S; Wright, William W; Dicandeloro, Paul et al. (2008) Stage-specific gene expression is a fundamental characteristic of rat spermatogenic cells and Sertoli cells. Proc Natl Acad Sci U S A 105:8315-20
Charron, Martin; Chern, Jing-Yi; Wright, William W (2007) The cathepsin L first intron stimulates gene expression in rat sertoli cells. Biol Reprod 76:813-24