Establishment of oocyte population in the fetal ovary: primordial germ cell proliferation and oocyte programmed cell death

Abstract

Strict control of cell proliferation and cell loss is essential for the coordinated functions of different cell populations in complex multicellular organisms. Oogenesis is characterized by a first phase occurring during embryo-fetal life and in common with spermatogenesis, during which mitotic proliferation of the germline stem cells, the primordial germ cells (PGC), prevails over germ cell death. The result is the formation of a relatively high number of germ cells depending on the species, ready to enter sex specific differentiation. In the female, PGC enter into meiosis and become oocytes, thereby ending their stem cell potential. After entering into meiosis in the fetal ovary, oocytes pass through leptotene, zygotene and pachytene stages before arresting in the last stage of meiotic prophase I, the diplotene or dictyate stage at about the time of birth. The most part of oocytes die during the fetal period or shortly after birth. It is widely accepted that in mammals a female is born with a fixed number of oocytes within the ovaries, which over the years progressively decreases without possibility for renewal. Once the oocyte reserve has been exhausted, ovarian senescence, driving what is referred to as the menopause in women, rapidly ensues. The fertile lifespan of a female depends by the size of the oocyte pool at birth and the rapidity of the oocyte pool depletion. Which mechanisms control PGC proliferation? Why do most of the oocytes die during fetal life and what are the mechanisms of such massive degeneration? Is it possible to prolong the lifespan of a female by reducing oocyte lost during the fetal life? This review reports some of the most recent results obtained in an attempt to answer these questions.

Quantification of healthy follicles in the neonatal and adult mouse ovary: evidence for maintenance of primordial follicle supply

“…In all the mammalian species studied, there is an oversupply of germ cells within the late fetal ovary (Coucouvanis et al 1993, Vaskivuo et al 2001, Vaskivuo & Tapanainen 2002. Depending on the species, many oocytes are eliminated by apoptosis prior to and at the time of birth (Ratts et al 1995, Reynaud & Driancourt 2000, Shirota et al 2003, De Felici 2004, and those that remain in the neonatal mouse ovary acquire and are surrounded by granulosa cells, establishing a pool of diplotene-arrested oocytes identified as primordial follicles (Pedersen 1969, Peters 1969. The enclosure of oocytes by granulosa cells during the first postnatal week of ovarian development exhibits temporal and spatial heterogeneity within the ovary, since larger diplotene-arrested oocytes that form primordial follicles first appear in the deep cortex and medulla (Byskov & Nielson 2003).…”

The promoter of the oocyte-specific gene, Gdf9, is active in population of cultured mouse embryonic stem cells with an oocyte-like phenotype

“…LIF has been widely studied as a media additive important for the maintenance of ES cells in a self-renewing, undifferentiated state [21][22][23][24]. However, based on several reports demonstrating the importance of LIF not only in the survival and self-renewal of PGCs [25][26][27]44], but also in the maturation of oocytes and ovarian follicles [26,28,31,45], we decided to study its role in the formation of germ cells from ES cells in vitro. We found that LIF, when added to the media of ES cells differentiating in the absence of a MEF monolayer, significantly increased not only the number of eGFP-positive oocyte-like cells, but also the expression of oocyte specific genes in vitro.…”

“…We first focused our attention on the media additive LIF. While LIF has been extensively studied as an important factor in stem cell self-renewal [21][22][23][24], several studies have reported the importance of LIF in the development of primordial and primary follicles of the ovary and have determined LIF is necessary for oocyte maturation [25][26][27][28][29]. PGK12.1 XX ES cells transfected with the Gdf9/eGFP were grown on a MEF monolayer in the presence of LIF for two days.…”

Apoptosis in the germ line

“…Once in the gonadal anlage, the primordial germ cells migrate centrally forming primitive sex cords after which they cease motility and are called oogonia. However, these cells proliferate extensively during their migration and continue to do so as oogonia after colonization of the gonads (De Felici et al 2005). The oogonia then begin forming nests, beginning at E10.5 in mice, and are connected by intercellular bridges.…”