title: Mouse Spermatogenesis Requires Classical and Nonclassical Testosterone Signaling.
abstract: Testosterone acts though the androgen receptor in Sertoli cells to support germ cell development (spermatogenesis) and male fertility, but the molecular and cellular mechanisms by which testosterone acts are not well understood. Previously, we found that in addition to acting through androgen receptor to directly regulate gene expression (classical testosterone signaling pathway), testosterone acts through a nonclassical pathway via the androgen receptor to rapidly activate kinases that are known to regulate spermatogenesis. In this study, we provide the first evidence that nonclassical testosterone signaling occurs in vivo as the MAP kinase cascade is rapidly activated in Sertoli cells within the testis by increasing testosterone levels in the rat. We find that either classical or nonclassical signaling regulates testosterone-mediated Rhox5 gene expression in Sertoli cells within testis explants. The selective activation of classical or nonclassical signaling pathways in Sertoli cells within testis explants also resulted in the differential activation of the Zbtb16 and c-Kit genes in adjacent spermatogonia germ cells. Delivery of an inhibitor of either pathway to Sertoli cells of mouse testes disrupted the blood-testis barrier that is essential for spermatogenesis. Furthermore, an inhibitor of nonclassical testosterone signaling blocked meiosis in pubertal mice and caused the loss of meiotic and postmeiotic germ cells in adult mouse testes. An inhibitor of the classical pathway caused the premature release of immature germ cells. Collectively, these observations indicate that classical and nonclassical testosterone signaling regulate overlapping and distinct functions that are required for the maintenance of spermatogenesis and male fertility.
authors.affiliation: Center for Research in Reproductive Physiology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Corey
authors.initials: C
authors.lastname: Toocheck
authors.affiliation: Center for Research in Reproductive Physiology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Terri
authors.initials: T
authors.lastname: Clister
authors.affiliation: Center for Research in Reproductive Physiology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: John
authors.initials: J
authors.lastname: Shupe
authors.affiliation: Center for Research in Reproductive Physiology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Crum
authors.affiliation: Department of Urology, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas.
authors.forename: Preethi
authors.initials: P
authors.lastname: Ravindranathan
authors.affiliation: Department of Chemistry, University of Texas, Dallas, Richardson, Texas.
authors.forename: Tae-Kyung
authors.initials: TK
authors.lastname: Lee
authors.affiliation: Department of Chemistry, University of Texas, Dallas, Richardson, Texas.
authors.forename: Jung-Mo
authors.initials: JM
authors.lastname: Ahn
authors.affiliation: Department of Urology, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
authors.affiliation: Center for Research in Reproductive Physiology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Meena
authors.initials: M
authors.lastname: Sukhwani
authors.affiliation: Center for Research in Reproductive Physiology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Orwig
authors.affiliation: Center for Research in Reproductive Physiology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania walkerw@pitt.edu.
authors.forename: William H
authors.initials: WH
authors.lastname: Walker
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005298:Fertility / Q000187:drug effects / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics; D012708:Sertoli Cells / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013091:Spermatogenesis / Q000187:drug effects / Q000502:physiology*; D013737:Testis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011944:Receptors, Androgen; C490383:Rhox5 protein, rat; D014157:Transcription Factors; C534029:ZBTB16 protein, rat; D013739:Testosterone; D019009:Proto-Oncogene Proteins c-kit; D020928:Mitogen-Activated Protein Kinases
keywords: Sertoli cell; androgen receptor; fertility; nongenomic; testis