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Evidence for a Role of Glycogen Synthase Kinase-3ß in Rodent Spermatogenesis

HARRI HAKOVIRTA^,

YANG XIAO

JORMA TOPPARI^,||

AARON P. MITCHELL

From the ^* Department of Medicine, Division of Endocrinology, Harbor-UCLA Medical Center and Research and Education Institute, Torrance, California; the Departments of Physiology, Surgery, and^|| Pediatrics, University of Turku, Turku, Finland; and the Department of Microbiology and Institute of Cancer Research, Columbia University, New York, New York.

Correspondence to: Dr Wael A. Salameh, Division of Endocrinology, Harbor–UCLA Medical Center, Box 446, 1000 W Carson St, Torrance, CA 90509 (e-mail: wsalameh{at}gcrc.rei.edu).

Glycogen synthase kinase-3ß (GSK-3ß) regulates cell metabolism, cell cycle, and cell fate through the phosphorylation of a diverse array of substrates. Herein, we provide evidence that supports a role for GSK-3 in mammalian meiosis and spermatogenesis. Immunostaining of testis sections showed that while GSK-3 was ubiquitous in the seminiferous tubules, GSK-3ß was expressed in premeiotic type B spermatogonia, in both meiotic preleptotene and leptotene spermatocytes, as well as in Sertoli cells in both the mouse and rat. Thus, GSK-3ß is expressed in germ cells entering meiosis. In addition, intense immunoreactivity was detected in rat step 6 though 11 spermatids. In situ hybridization (ISH) in rat testis confirmed the immunostaining pattern in leptotene and spermatids and showed a GSK-3ß messenger RNA (mRNA) signal in some pachytene spermatocytes. The restricted pattern of expression suggests cell-specific regulation of Gsk-3ß mRNA. To determine whether GSK-3 is required for meiosis entry, rat stage VIIa seminiferous tubule segments were cultured with selective small-molecule GSK-3 inhibitors. These compounds markedly and dose-dependently suppressed meiotic synthesis (S)-phase DNA. Since a yeast GSK-3 homolog, Rim11p (regulator of inducer of meiosis), is pivotal to meiosis entry, we tested whether GSK-3ß complements Rim11p function in meiosis. Rim11p phosphorylates transcription factors Ume6p (unscheduled meiotic gene expression) and Ime1p (inducer of meiosis) to induce meiosis entry. Overexpression of murine GSK-3ß in a rim11 mutant yeast failed to rescue the sporulation defect. Our finding that GSK-3ß interacted only with Ume6p but not with IME1 in a yeast 2-hybrid assay suggests that noncomplementation reflects partial divergence in substrate specificity. This work provides the basis for future studies of GSK-3ß signaling in mammalian meiosis and spermatogenesis.

     Key words: Testis, meiosis, tubule culture, Rim11p

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