help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Morita, Y.
Right arrow Articles by Tilly, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Morita, Y.
Right arrow Articles by Tilly, J. L.
Endocrinology Vol. 140, No. 6 2696-2703
Copyright © 1999 by The Endocrine Society

ARTICLES

Segregation of Retinoic Acid Effects on Fetal Ovarian Germ Cell Mitosis Versus Apoptosis by Requirement for New Macromolecular Synthesis1

Yutaka Morita2 and Jonathan L. Tilly

Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Jonathan L. Tilly, Ph.D., Massachusetts General Hospital, VBK137E-GYN, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: jtilly{at}partners.org

Retinoic acid (RA), a naturally occurring metabolite of vitamin A, plays an essential role in regulating cellular growth, differentiation, and death in a variety of tissues, particularly during fetal development. However, essentially nothing is known of the effects of RA on fetal gametogenesis. Using a recently validated system of culturing murine fetal ovaries, herein we sought to characterize the actions of RA on female germ cell proliferation and apoptosis during oogenesis. In the absence of trophic hormone support, approximately 90% of the oogonia and oocytes present in fetal ovaries at the start of culture underwent apoptosis over a 72 h culture period (P < 0.05), whereas provision of 0.01–1 µM RA dose dependently maintained germ cell numbers. In fact, ovaries cultured with 0.1 µM RA for 72 h possessed approximately 30% more oogonia and oocytes as compared with the preculture mean number (P < 0.05). Additional experiments, using in situ DNA 3'-end-labeling and cellular morphology to assess apoptosis coupled with 5-bromo-2'-deoxyuridine incorporation to assess proliferation, revealed that RA acts as both a mitogen and a survival factor for female germ cells. Furthermore, the ability of RA to stimulate germ cell proliferation in cultured fetal ovaries was completely suppressed (P < 0.05) by cotreatment with inhibitors of transcription ({alpha}-amanitin, 0.1 µg/ml) or protein synthesis (cycloheximide, 1.0 µg/ml), whereas RA-mediated suppression of germ cell apoptosis was not affected by cotreatment with either macromolecular synthesis inhibitor (P > 0.05). Moreover, cotreatment of fetal ovaries with 5 µM LY294002, an inhibitor of phosphatidylinositol 3'-kinase, had no effect on RA-promoted germ cell maintenance (P > 0.05). By comparison, the antiapoptotic effects of insulin-like growth factor I on germ cells in cultured fetal ovaries were significantly attenuated by cotreating ovaries with LY294002 (P < 0.05) but not with {alpha}-amanitin or cycloheximide (P > 0.05). Importantly, the effect of RA on the female germ line was also observed in vivo because a single oral administration of 100 mg/kg RA to timed-pregnant female mice resulted in a significantly (P < 0.05) larger endowment of primordial oocytes in female offspring. That these actions were mediated, at least in part, by specific retinoid receptors was demonstrated by the finding of retinoic acid receptor protein in fetal female gonocytes, as assessed by immunohistochemical localization experiments. Collectively, these data indicate that RA can function, in vitro and in vivo, as a potent germ cell survival factor and mitogen during fetal oogenesis in the mouse.




This article has been cited by other articles:


Home page
 Hum ReprodHome page
F. Ghafari, S. Pelengaris, E. Walters, and G.M. Hartshorne
Influence of p53 and genetic background on prenatal oogenesis and oocyte attrition in mice
Hum. Reprod., June 1, 2009; 24(6): 1460 - 1472.
[Abstract] [Full Text] [PDF]

Home page
 Mol Hum ReprodHome page
A. Kocer, J. Reichmann, D. Best, and I. R. Adams
Germ cell sex determination in mammals
Mol. Hum. Reprod., April 1, 2009; 15(4): 205 - 213.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
L. Levi, B. Levavi-Sivan, and E. Lubzens
Expression of Genes Associated with Retinoid Metabolism in the Trout Ovarian Follicle
Biol Reprod, September 1, 2008; 79(3): 570 - 577.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
J. Bowles and P. Koopman
Retinoic acid, meiosis and germ cell fate in mammals
Development, October 1, 2007; 134(19): 3401 - 3411.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
M. Alton and T. Taketo
Switch from BAX-dependent to BAX-independent germ cell loss during the development of fetal mouse ovaries
J. Cell Sci., February 1, 2007; 120(3): 417 - 424.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
J. Bowles, D. Knight, C. Smith, D. Wilhelm, J. Richman, S. Mamiya, K. Yashiro, K. Chawengsaksophak, M. J. Wilson, J. Rossant, et al.
Retinoid Signaling Determines Germ Cell Fate in Mice
Science, April 28, 2006; 312(5773): 596 - 600.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. Koubova, D. B. Menke, Q. Zhou, B. Capel, M. D. Griswold, and D. C. Page
Inaugural Articles: Retinoic acid regulates sex-specific timing of meiotic initiation in mice
PNAS, February 21, 2006; 103(8): 2474 - 2479.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
K.-H. Tung, L. R. Wilkens, A. H. Wu, K. McDuffie, J. H. Hankin, A. M.Y. Nomura, L. N. Kolonel, and M. T. Goodman
Association of Dietary Vitamin A, Carotenoids, and Other Antioxidants with the Risk of Ovarian Cancer
Cancer Epidemiol. Biomarkers Prev., March 1, 2005; 14(3): 669 - 676.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
R.-Z. Liu, Q. Sun, C. Thisse, B. Thisse, J. M. Wright, and E. M. Denovan-Wright
The Cellular Retinol-Binding Protein Genes Are Duplicated and Differentially Transcribed in the Developing and Adult Zebrafish (Danio rerio)
Mol. Biol. Evol., March 1, 2005; 22(3): 469 - 477.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
E.-H. Park and T. Taketo
Onset and Progress of Meiotic Prophase in the Oocytes in the B6.YTIR Sex-Reversed Mouse Ovary
Biol Reprod, December 1, 2003; 69(6): 1879 - 1889.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
T. M. Matikainen, T. Moriyama, Y. Morita, G. I. Perez, S. J. Korsmeyer, D. H. Sherr, and J. L. Tilly
Ligand Activation of the Aromatic Hydrocarbon Receptor Transcription Factor Drives Bax-Dependent Apoptosis in Developing Fetal Ovarian Germ Cells
Endocrinology, February 1, 2002; 143(2): 615 - 620.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 1999 by The Endocrine Society