Perspective: The Ovarian Follicle--A Perspective in 2001

Abstract

In the past century, tremendous progress has been made in our understanding of the endocrine regulation of fertility. The identification and purification of peptide and steroid hormones and our knowledge of their actions in endocrine cells has led to major advances in contraceptive development, in vitro fertilization, and endocrine therapy. The advances in molecular biology have led to our understanding of how hormones and growth factors regulate the expression of specific genes in endocrine cells. Today, the disruption and deletion of selected genes in mice is becoming routine and null mutations for many proteins expressed in and regulating endocrine cell function have been generated. These mutant mice have brought molecular reproductive endocrinologists full circle. We have returned to ablation-replacement bioassays used by the early endocrinologists, albeit in a much more sophisticated way and with more elaborate and specific mechanisms. The new age endocrinology and our knowledge of endocrine cell function will expand even more explosively now that the cloning of the mouse and human genomes nears completion. In the next century, new hormones, new receptors, new signaling pathways for old receptors, and new transcription factors will no doubt be identified and our understanding of the complex pathways regulating endocrine cells should be markedly enhanced. The goal of this minireview is to highlight some recent advances in our knowledge of how hormones and growth factors impact the formation and growth as well as the termination of the ovarian follicle. Of particular relevance is the importance of the microenvironments that control oocyte-cumulus cell functions and granulosa-theca cell functions within the follicle and how hormones, such as FSH and LH, impact these microenvironments. Highlighting what we know about the ovarian follicle in 2001 may help us set goals for 2100. Hopefully, basic science and clinical discoveries in the next century will unravel the endocrine, molecular, and cellular bases of premature ovarian failure, polycystic ovarian syndrome, and ovarian cancer. The formation of primordial follicles depends on the presence of the female germ cells, the oocytes, and their interactions with surrounding somatic cells, the pregranulosa cells. Our current knowledge of the genes and factors that control gonadogenesis and oocyte migration to the genital ridge is increasing but still remains relatively limited (1, 2). Members of the transforming growth factor-β (TGFβ) family appear to be key regulators of ovarian organization and development at several stages. Bmp4 and Bmp8b, which are produced by the extraembryonic ectoderm are essential for the generation of primordial germ cells (PMGs) (3) (Figs. 1 and 2). Once germ cells are formed, gonadal development is regulated by the expression of specific transcription factors in the somatic cells of the indifferent gonad (Fig. 1). Among these factors are Lhx1, Lhx9, WT1, Wnt 4, and the orphan nuclear transcription factor steroidogenic factor-1 (SF-1) (1, 4, 5) (Figs. 1 and 2). Although originally cloned and identified as a transcription factor that regulates steroid hydroxylase genes, it is clear that SF-1 has other functions. Mice null for SF-1 have no gonads, no adrenal and altered pituitary and hypothalamic function, corresponding to sites of its expression in somatic cells of these tissues (5, 6). SF-1 has now been shown to regulate transcription of many genes including, Müllerian-inhibiting substance (MIS) (7, 8), LHβ (9) and the FSH receptor (10) to name a few. Expression of SF-1 and the FSH receptor are also mediated by the E-box binding transcription factor upstream stimulatory factor (USF) (11–13), which also regulates such diverse genes as RIIβ the regulatory subunit of type II cAMP-dependent protein kinase and COX-2 cyclo-oxygenase-2 (14). In addition, transcription of SF-1 and MIS, as well as other gonadal genes, is regulated by members of the GATA family of transcription factors of which GATA-4 and GATA-6 are expressed in granulosa cells of developing follicles (15, 16). Schematic of expression and interactions of local organizers and external impact factors that control ovarian follicular development. Follicular development is dependent on sequential changes in local organizing factors (listed vertically for each stage of follicular development), cell-cell interactions as well as on external impact factors such as the pituitary gonadotropins FSH and LH. Formation of primordial germ cells (PGCs) occurs as a consequence of signals (Bmp4 and Bmp8) from the extraembryonic ectoderm (EEE) as well as cell-cell interactions via gap junctions, connexin 43. Somatic cells of the embryonic gonad determine gonadal sex and viability of the oocytes. Some factors involved in this process include Kit ligand KL, SF-1, Wilms tumor suppressor 1 (WT1), and Wnt 4 as well as connexin 43. After gonadogenesis, oocytes within primordial follicles express various