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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 6 2644-2657
Copyright © 2002 by The Endocrine Society

The Impact of the Human Genome on Endocrinology: Original Articles

Localization of the Activin Signal Transduction Components in Normal Human Ovarian Follicles: Implications for Autocrine and Paracrine Signaling in the Ovary

Stephanie A. Pangas, Alfred W. Rademaker, David A. Fishman and Teresa K. Woodruff

Department of Neurobiology and Physiology (S.A.P., T.K.W.), Northwestern University, Evanston, Illinois 60208; and Departments of Preventative Medicine (A.W.R.), Obstetrics and Gynecology (D.A.F.), and Medicine (T.K.W.), Northwestern University Medical School, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Teresa K. Woodruff, Ph.D., Department of Neurobiology and Physiology, Northwestern University, 2153 North Campus Drive, Evanston, Illinois 60208.

Abstract

The intraovarian function of gonadally produced activin is unclear, and many in vitro studies have suggested a role for activin in follicle development. To identify the follicular developmental stages at which these ligands may be acting, we have used immunohistochemical localization of the ligand subunits, receptor subtypes, and Smad co-activating proteins within the same follicles. The earliest stages of follicle development (primordial to primary) show no immunoreactivity for the activin subunits or their receptors. Oocytes from these early stages contain immunostaining for Smad2 and Smad4, consistent with signaling by other TGF-ß superfamily members. Immunostaining for the activin type II receptor first appears in oocytes and oocyte-associated cumulus cells at the secondary follicle stage. However, activin is not produced in these follicles, suggesting that either the receptors are inactive at this stage or they are used by another protein. Co-localization of activin and inhibin subunits, receptors, and Smads only occurs in granulosa and theca cells of small antral, aromatase-positive follicles as well as granulosa cells of early atretic follicles. In addition, multivariate statistical analysis reveals that the ligands and their cellular signaling complexes are independently regulated. Together, these data strongly suggest that the intraovarian role of activin is limited to a few developmental stages and that other TGF-ß family members may use this cell autonomous signaling machinery in early follicle development.




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