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Identification of a Nuclear Localization Signal in Activin/Inhibin ß_A Subunit; Intranuclear ß_A in Rat Spermatogenic Cells¹

^a Molecular Endocrinology Research Unit and Graduate School of Steroid Research, Department of Anatomy, Medical School, University of Tampere, Tampere, Finland ^b Department of Clinical Chemistry, Tampere University Hospital, Tampere, Finland ^c Institute of Medical Technology, University of Tampere, FIN-33101 Tampere, Finland

Activin is a dimeric glycoprotein hormone that was initially characterized by its ability to stimulate pituitary FSH secretion and was subsequently recognized as a growth factor with diverse biological functions in a large variety of tissues. In the testis, activin has been implicated in the auto/paracrine regulation of spermatogenesis through its cognate cell membrane receptors on Sertoli and germ cells. In this study we provide evidence for intranuclear activin/inhibin ß_A subunit and show its distribution in the rat seminiferous epithelium. We have shown by transient expression in HeLa cells of ß-galactosidase fusion proteins that the ß_A subunit precursor contains a functional nuclear localization signal within the lysine-rich sequence corresponding to amino acids 231-244. In all stages of the rat seminiferous epithelial cycle, an intense immunohistochemical staining of nuclear ß_A was demonstrated in intermediate or type B spermatogonia or primary spermatocytes in their initial stages of the first meiotic prophase, as well as in pachytene spermatocytes and elongating spermatids primarily in stages IX–XII. In some pachytene spermatocytes, the pattern of ß_A immunoreactivity was consistent with the characteristic distribution of pachytene chromosomes. In the nuclei of round spermatids, ß_A immunoreactivity was less intense, and in late spermatids it was localized in the residual cytoplasm, suggesting disposal of ß_A before spermatozoal maturation. Immunoblot analysis of a protein extract from isolated testicular nuclei revealed a nuclear ß_A species with a molecular mass of approximately 24 kDa, which is more than 1.5 times that of the mature activin ß_A subunit present in activin dimers. These results suggest that activin/inhibin ß_A may elicit its biological functions through two parallel signal transduction pathways, one involving the dimeric molecule and cell surface receptors and the other an alternately processed ß_A sequence acting directly within the nucleus. According to our immunohistochemical data, ß_A may play a significant role in the regulation of nuclear functions during meiosis and spermiogenesis.

¹ This work was supported by grants from the Medical Research Fund of Tampere University Hospital and the University of Tampere.

² Correspondence: Merja Bläuer, Department of Anatomy, Medical School, University of Tampere, P.O. Box 607, FIN-33101 Tampere, Finland. FAX: 358 3 2156170; blauer{at}csc.fi

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