The primordial pool of follicles and nest breakdown in mammalian ovaries

Abstract

The creation of the pool of follicles available for selection and ovulation is a multi-faceted, tightly regulated process that spans the period from embryonic development through to the first reproductive cycle of the organism. In mice, this development can occur in mere weeks, but in humans, it is sustained for years. Embryonic germ cell development involves the migration of primordial germs cells to the genital ridge, and the mitotic division of germ cell nuclei without complete cytokinesis to form a multi-nucleated syncytia, or germ cell nest. Through combined actions of germ cell apoptosis and somatic cell migration, the germ cell nuclei are packaged, with surrounding granulosa cells, into primordial follicles to form the initial follicle pool. Though often dismissed as quiescent and possibly uninteresting, this initial follicle pool is actually quite dynamic. In a very strictly controlled mechanism, a large portion of the initial primordial follicles formed is lost by atresia before cycling even begins. Remaining follicles can undergo alternate fates of continued dormancy or selection leading to follicular growth and differentiation. Together, the processes involved in the fate decisions of atresia, sustained dormancy, or activation carve out the follicle pool of puberty, the pool of available oocytes from which all future reproductive cycles of the female can choose. The formation of the initial and pubertal follicle pools can be predictably affected by exogenous treatment with hormones or molecules such as activin, demonstrating the ways the ovary controls the quality and quantity of germ cells maintained. Here, we review the biological processes involved in the formation of the initial follicle pool and the follicle pool of puberty, address the alternate models for regulating germ cell number and outline how the ovary quality-controls the germ cells produced.

Figure 1

Molecular modifiers involved in female germ cell nest breakdown and subsequent primordial follicle fates. The breakdown of germ cell nest to form primordial follicles involves interplay of several molecular factors that control the timing and extent of the breakdown. Aberrant breakdown can lead to increased loss of germ cells or the formation of MOFs. Following their formation, primordial follicles have three separate possible fates: follicular atresia, transition to the growth phase or maintained primordial status. SCP1, synaptonemal complex protein-1; BMP, bone morphogenetic protein; GDF, growth differentiation factor; SCF, stem cell factor; bFGF, basic fibroblast growth factor; AMH, anti-Mullerian hormone; Figα, oocyte-specific transcription factor; Foxl2, forkhead box transcription factor; PTEN, phosphatase and tensin homolog, a tumor suppressor.

Figure 2

Alternative models for the creation and maintenance of the ovarian reserve. During the pre-pubertal period, primordial follicles are lost at a high rate that is slowed at the time of the FSH surge. Models where the number of initial follicles is increased show an increased rate of loss so that they reach typical numbers of follicles, indicating a quorum-sensing model with a ‘set point’ for follicle number. Stem cell supplementation models propose that the number of follicles can be increased throughout reproductive life. The Tilly stem cell model indicates a constant number of oocytes is created from stem cells. We favor a model in which the initial follicle pool is established at birth and these follicles are necessary to adult fertility (there are no additional follicles added to the pool) and sufficient to the fertility needs of the adult (follicle loss is not so much to prematurely lose all follicles.).