Genetics, Female Gametogenesis

Development

The process of gametogenesis occurs during fetal development, beginning with sexually dimorphic primordial germ cells within the ovaries of the fetus. These primordial germ cells migrate to the genital ridge, forming oogonia by mitotic proliferation. However, these germ cells are eventually committed to the transition from mitosis to meiosis; this process involves 1 round of DNA replication followed by 2 meiotic divisions, aptly named meiosis I and meiosis II. Meiosis begins with an oocyte containing 2 homologous copies of each of the 23 chromosomes; 1 copy is inherited from the father and 1 from the mother. Each chromosome replicates to form 2 sister chromatids during the S phase of meiosis I. After the S phase, a phenomenon called meiotic recombination occurs, during which DNA double-strand breaks (DSBs) are created, allowing for the exchange of genetic material between homologous chromosomes. Meiotic recombination increases the genetic diversity of developing gametes and forms a physical connection that aids in keeping homologous chromosomes together. It is important to note that correct meiotic chromosome segregation is ensured, in part, by the connection maintained between chromatids, which allow genetic recombination. This connection is maintained from its establishment in prophase I until the eventual separation of homologous chromosomes after metaphase I.[1][2][3][4][5]

In contrast to male gametogenesis, developing female gametes do not proceed directly through to meiosis II. Instead, around the time of birth, the developing oocytes enter a prolonged resting phase during the meiotic prophase I, called the dictyate. This period can last for decades while the oocyte remains arrested within an ovarian follicle, termed a primary ovarian follicle. The growing follicle consists of the developing oocyte, 1 or several layers of surrounding somatic cells called granulosa cells, and an outer rim of specialized cells called theca cells. Gap junctions are also present between the oocyte and the granulosa cells, allowing for the transfer of nutrients and communication via second messenger molecules, contributing to the early stages of follicular maturation (before hormonal stimulation).[1][5]

Hormonal stimulation during the adult estrous cycle is also responsible for follicular maturation and the progression of the developing oocyte into meiosis II. Initially, the follicle containing the arrested oocyte responds to stimulation from follicle-stimulating hormone (FSH) secreted by the pituitary gland, which binds to FSH receptors located on the granulosa cells, causing the growth and maturation of the follicle into a secondary ovarian follicle. This event marks the beginning of the secondary follicular phase, which further subdivides into a pre-antral and antral phase depending on the timing of the antrum formation within the follicle as the granulosa cells and theca cells proliferate. FSH is the primary driver of antral development within the follicle and causes increased expression of luteinizing hormone (LH) receptors. Additionally, follicles stimulated by gonadotropins synthesize steroid hormones such as androgens and estrogens (primarily estradiol), further contributing to follicular development in a paracrine/autocrine fashion. Most importantly, for oocyte maturation, FSH stimulation leads to the differentiation of granulosa cells into 2 separate cellular compartments named the cumulus and mural compartments, thus conferring to the arrested oocyte to continue meiosis I until it is arrested again in metaphase II. The growing ovarian follicle becomes stimulated to release the oocyte in response to the surge of LH secreted by the pituitary gland. This surge gives rise to the event of ovulation, during which the follicular wall ruptures, and the cumulus-oocyte complex is released. This event also leads to the formation of luteal cells from the granulosa and theca cells, which serve to secrete estradiol and, primarily, progesterone. The mature oocyte, now arrested in metaphase II, only completes meiosis II in the event of fertilization by a male spermatozoon, forming a zygote.[6]

Cellular

The major cellular process behind gametogenesis is meiosis, which involves the division of 1 diploid (2n) cell into 4 haploid (1n) copies. Meiotic division occurs after DNA replication in oogonia (or spermatogonia). Two meiotic divisions follow DNA replication, neither of which includes additional intervening DNA synthesis. The first division separates homologous chromosome pairs, while the second division separates the sister chromatids. It is important to note that, in contrast to male gametogenesis, the cytoplasmic divisions are grossly unequal, with one half receiving the vast majority of the cytoplasmic contents and the remaining product (designated polar bodies) receiving a much smaller amount of cytoplasm. This asymmetrical division of resources ensures adequate nutrients for the embryo after fertilization.[7]

Function

The end product of female gametogenesis is a healthy and mature oocyte, which is released from the follicle during ovulation to join with a male gamete through fertilization. The function of the mature oocyte is to provide half of the genetic material to the zygote formed through fertilization, as well as the intracellular components and organelles needed for maturation and future division.[6]

Pathophysiology

Incorrect gametogenesis can lead to several pathologies, although an exhaustive discussion is not covered here. It is worth noting that aneuploidy is more common in female gametogenesis despite the higher rate of recombination also seen during female gametogenesis compared to gametogenesis in males. Errors resulting in aneuploidy, regardless of etiology, unsurprisingly, lead to fetal chromosomal abnormalities such as Down Syndrome as well as miscarriage and age-related infertility. Meiosis I, in particular, is associated with age-related increases in chromosomal missegregation. Although aneuploidy, in general, is most likely multi-factorial, the age-related decline in the presence of cohesive molecules holding chromosomes together during meiosis leads to a predisposition of becoming aneuploid via nondisjunction of homologous chromosomes. In rare instances, nutritional defects during the differentiation of oocytes can interfere with their fertilization, causing a hydatidiform mole leading to gestational trophoblastic disease.[1][8][9][10]

Clinical Significance

As discussed above in the section on pathophysiology, there are many clinically significant manifestations of incorrect female gametogenesis. Fetal chromosomal abnormalities, gestational trophoblastic disease, and age-related infertility can all be directly linked back to aberrant gametogenesis within the ovaries.[10][9][8]