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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2008-0134v1 26/11/2928    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Google Scholar Articles by Dann, C. T. Articles by Porteus, M. H. PubMed PubMed Citation Articles by Dann, C. T. Articles by Porteus, M. H.

TISSUE-SPECIFIC STEM CELLS

Spermatogonial Stem Cell Self-Renewal Requires OCT4, a Factor Downregulated During Retinoic Acid-Induced Differentiation

Departments of ^aPediatrics and
^bPharmacology,
^cGreen Center for Reproductive Biology Sciences, and
^dHoward Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA

Key Words. Spermatogonia • OCT4 • Pou5f1 • RNA interference • Retinoic acid • Stem cell transplantation

Correspondence: Christina Tenenhaus Dann, Ph.D., Chemistry Building 115, 800 E. Kirkwood Avenue, Bloomington, IN 47405-7102, USA. Telephone: 812-855-0821; Fax: 812-855-8300; e-mail: ctdann{at}indiana.edu

Received February 12, 2008; accepted for publication August 11, 2008.
First published online in STEM CELLS EXPRESS   August 21, 2008.

The long-term production of billions of spermatozoa relies on the regulated proliferation and differentiation of spermatogonial stem cells (SSCs). To date only a few factors are known to function in SSCs to provide this regulation. Octamer-4 (OCT4) plays a critical role in pluripotency and cell survival of embryonic stem cells and primordial germ cells; however, it is not known whether it plays a similar function in SSCs. Here, we show that OCT4 is required for SSC maintenance in culture and for colonization activity following cell transplantation, using lentiviral-mediated short hairpin RNA expression to knock down OCT4 in an in vitro model for SSCs ("germline stem" [GS] cells). Expression of promyelocytic leukemia zinc-finger (PLZF), a factor known to be required for SSC self-renewal, was not affected by OCT4 knockdown, suggesting that OCT4 does not function upstream of PLZF. In addition to developing a method to test specific gene function in GS cells, we demonstrate that retinoic acid (RA) triggers GS cells to shift to a differentiated, premeiotic state lacking OCT4 and PLZF expression and colonization activity. Our data support a model in which OCT4 and PLZF maintain SSCs in an undifferentiated state and RA triggers spermatogonial differentiation through the direct or indirect downregulation of OCT4 and PLZF. The current study has important implications for the future use of GS cells as an in vitro model for spermatogonial stem cell biology or as a source of embryonic stem-like cells.

Disclosure of potential conflicts of interest is found at the end of this article.