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Consequences of Fetal Irradiation on Follicle Histogenesis and Early Follicle Development in Rat Ovaries¹

Laboratoire de Physiologie et Physiopathologie, CNRS-UMR 7079, Université Paris VI, 75252 Paris cedex 05, France

ABSTRACT

Follicle histogenesis, in which follicles arise from fragmenting ovigerous cords, is a poorly understood mechanism that is strictly dependent upon the presence of germ cells. Our previous studies have shown that severely germ cell-depleted rat ovaries after fetal gamma-irradiation display modifications of follicular endowment and dynamics during the immature period. The primordial follicle stock was absent and the follicles with primary appearance remained quiescent longer than in control ovaries during the neonatal period. The aim of the present work was to analyze the initial steps of follicle histogenesis, and to investigate the etiology of the alterations observed in the development of irradiated ovaries. Just after birth, we observed, in addition to sterile ovigerous cords, the emergence of the first follicles which exhibited several abnormal features as compared to those of control ovaries. Most of the follicles appeared as primary follicles, as they were composed of a layer of cuboidal-shaped granulosa cells surrounding an enlarged oocyte. Interestingly, the granulosa cells of these primary-like follicles did not proliferate and did not express the genes for anti-Müllerian hormone (Amh) or bone morphogenetic protein receptor type II (Bmpr2), both of which are normally expressed from the primary stage onwards. In contrast, the oocytes strongly expressed the gene for growth and differentiation factor 9 (Gdf9), which is normally upregulated from the primary follicle stage onwards, which suggests an uncoupling of granulosa cell development from oocyte development. In addition, irradiated ovaries displayed a higher frequency of follicles that contained 2 or 3 oocytes, which are also referred to as multi-oocyte follicles (MOFs). Examination at the time of follicle histogenesis indicated that MOFs arise from incomplete ovigerous cord breakdown. Taken together, the results of this study indicate that severe perturbations of follicular histogenesis take place following irradiation and massive germ cell depletion during fetal life. In addition to the classically described sterile cords, we have pointed out the differentiation of MOFs and primary-like quiescent follicles, which finally evolve into growing follicles and participate in ovarian function. We propose that these phenotypes are closely correlated to the proportion of granulosa cells to oocytes at the time of neonatal follicle histogenesis.

developmental biology, follicle, follicular development, granulosa cells, ovary

² Correspondence: S. Magre, Laboratoire de Physiologie et Physiopathologie, UMR 7079, Université Paris VI, cc 256, 7 quai Saint-Bernard, 75005 Paris, France. FAX: 331 4427 2650; solange.magre{at}snv.jussieu.fr

³ Current address: Ontogeny-Reproduction Research Unit, Room T1–49, Centre Hospitalier Universitaire de Quebec (CHUQ)- Laval Research University Centre (CHUL), 2705 Laurier Boulevard, Ste-Foy, Quebec, Canada G1V 4G2.

⁴ Current address: Gene Regulation Section, Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.

¹ Supported by Electricité de France and the Ministère de l'Education Nationale et de la Recherche Scientifique et Technique (MENRST, France). S.M.G. is a recipient of a fellowship from Organon (Akzo Nobel, France).