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Proliferation of Adult Sertoli Cells Following Conditional Knockout of the Gap Junctional Protein GJA1 (Connexin 43) in Mice¹

Department of Veterinary Biosciences,³ University of Illinois at Urbana-Champaign, Urbana, Illinois 61802 INRS-Institut Armand Frappier,⁴ Université du Québec, Pointe Claire, Quebec, Canada H9R 1G6 Leon H. Charney Division of Cardiology,⁵ New York University School of Medicine, New York, New York 10016 UMR 6175 Institut National de la Recherche Agronomique,⁶ Centre National de Recherche Scientifique, Université de Tours, Haras Nationaux Physiologie de la Reproduction et des Comportements, 37380 Nouzilly, France

ABSTRACT

GJA1 (also known and referred to here as connexin 43 and abbreviated CX43) is the predominant testicular gap junction protein, and CX43 may regulate Sertoli cell maturation and spermatogenesis. We hypothesized that lack of CX43 would inhibit Sertoli cell differentiation and extend proliferation. To test this, a Sertoli cell-specific Cx43 knockout (SC-Cx43 KO) mouse was generated using Cre-lox technology. Immunohistochemistry indicated that CX43 was not expressed in the Sertoli cells of SC-Cx43 KO mice, but was normal in organs such as the heart. Testicular weight was reduced by 41% and 76% in SC-Cx43 KO mice at 20 and 60 days, respectively, vs. wild-type (wt) mice. Seminiferous tubules of SC-Cx43 KO mice contained only Sertoli cells and actively proliferating early spermatogonia. Sertoli cells normally cease proliferation at 2 wk of age in mice and become terminally differentiated. However, proliferating Sertoli cells were present in SC-Cx43 KO but not wt mice at 20 and 60 days of age. Thyroid hormone receptor alpha (THRA) is high in proliferating Sertoli cells, then declines sharply in adulthood. Thra mRNA expression was increased in 20-day SC-Cx43 KO vs. wt mice, and it showed a trend toward an increase in 60-day mice, indicating that loss of CX43 in Sertoli cells inhibited their maturation. In conclusion, we have generated mice lacking CX43 in Sertoli cells but not other tissues. Our data indicate that CX43 in Sertoli cells is essential for spermatogenesis but not spermatogonial maintenance/proliferation. SC-Cx43 KO mice showed continued Sertoli cell proliferation and delayed maturation in adulthood, indicating that CX43 plays key roles in Sertoli cell development.

cytokines, gamete biology, Sertoli cell differentiation and proliferation, spermatogenesis, spermatogonia, testis

¹Supported by the Billie A. Field Endowment, University of Illinois (P.S.C.), National Institutes of Health grants HL64757 (G.I.F.) and HL081336 (D.E.G.), and a Grant-in-Aid from the American Heart Association (D.E.G.). The work at the University of Illinois was conducted in a facility constructed with support from Research Facilities Improvement Program grant number C06 RR16515 from the National Center for Research Resources, National Institutes of Health.

Correspondence: ²Paul S. Cooke, Department of Veterinary Biosciences, University of Illinois at Urbana-Champaign, 2001 South Lincoln Avenue, Urbana, IL 61802. FAX: 217 244 1652; e-mail: p-cooke{at}uiuc.edu