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4.2.1 Males

Male germ cell differentiation occurs continuously in the seminiferous tubules of the testes throughout the life of a normal animal. This process has been very well characterized in the mouse (Bellvé et al., 1977; Eddy et al., 1991), and only its salient features will be summarized here. Spermatogenic cells at different stages are classified into four broad categories — spermatogonia, spermatocytes, spermatids, and spermatozoa — with numerous substages defined within each category. All pre-meiotic cells are called spermatogonia; these include regenerating stem cells as well as those that have taken the path to terminal differentiation. With the commencement of meiosis, germ cells are called spermatocytes, and subsequent to meiosis, haploid cells are called spermatids. Finally, with the release of the morphologically mature product, the germ cells are called spermatozoa or, more simply, just sperm.

The timing of the stages of spermatogenesis in the mouse was described originally by Oakberg (1956a; 1956b). At birth, the testis contains only undifferentiated type A1 spermatogonia, which will serve as a self-renewing stem cell population throughout the life of a male mouse. By day three, differentiation has begun through a series of mitotic divisions into more advanced spermatogonial stages (A2, A3, A4, intermediate and type B spermatogonia). By 8 to 10 days, spermatocytes are observed for the first time in the leptotene phase of meiosis (Nebel et al., 1961). The meiotic phase is relatively long, extending over a 13 day period. When the male has reached 17 to 19 days of age, approximately 50% of the seminiferous tubules are found to contain cells in the late pachytene stage. The earliest postmeiotic cells — round spermatids — are not observed until after 20 days (Nebel et al., 1961). During the next 13 days, the round spermatids differentiate into elongating spermatids in which the sperm tail forms and the nucleus condenses. At the end of this process, morphologically-mature sperm are released into the fluid-filled lumen.

The entire process of differentiation from stem cell to released spermatozoa is called spermatogenesis. The term spermiogenesis refers specifically to the final morphological differentiation of haploid cells into sperm. At the time of release into the lumen of the seminiferous tubules, sperm cells are still not physiologically mature. After leaving the testes, they pass through the epididymis where they undergo further biochemical changes. From the epididymis, they go to the vas deferens, where they are stored until ejaculation. The final stage of sperm maturation — known as capacitation — is required for fertilizing activity and does not occur until after contact has been made with the milieu of the female reproductive tract.

4.2.2 Females

Female germ cell differentiation operates under a two-phase time course dramatically different from that found in the male. 23 By the twelfth or thirteenth day after fertilization, the primordial oocytes within the fetal ovary have undergone their last mitotic division and are referred to as oogonia. At this point, the young female, still not born, has produced all of the germ cells that she will ever have; the total number is somewhere between 30,000 and 75,000. All of these oogonia progress into meiosis, and by five days after birth, they reach the diplotene stage of prophase of the first meiotic division. At this point, also called the dictyate stage, the oogonia become arrested and remain quiescent until sexual maturation. As they move into the dictyate stage, all primordial oocytes acquire a coat of follicle cells; the complete coat surrounding each oocyte is called a follicle.

With the onset of puberty, the ovaries become activated by hormone stimulation, and every 4 days, a new group of oogonia are stimulated to proceed forward toward their ultimate differentiated state. This second phase of differentiation occurs over a period of 20 days. During this entire period — until a few hours prior to ovulation — the oocytes still remain fixed in the dictyate stage of meiosis, but they become highly active metabolically and increase greatly in size from 15 to 80 microns. The size of each follicle also increases through the addition of follicle cells up to a total of 50,000 per ovum. At 20 days after activation, oocytes have become competent for ovulation, which occurs in response to the correct hormonal cues during the estrus cycle described in the next section. During each natural cycle, only 6-16 oocytes are stimulated to undergo ovulation. The stimulated follicles swell with fluid and move to the periphery of the ovary where they burst out to begin their journey into the oviduct and further down the reproductive tract.

Stimulation to ovulate also releases the oocyte (now also called an egg) from its state of arrest and induces it to continue through meiosis. The first meiotic division is completed and the first polar body is formed prior to release from the ovary. The second meiotic division begins immediately but stops at metaphase, where the oocyte remains arrested until fertilization. Penetration by the sperm triggers completion of the final meiotic division and the formation of the second polar body.

Surprisingly, at least 50% of the oocytes present at birth degenerate before the mouse reaches three weeks of age. The vast majority of the remaining oocytes are never ovulated — many degenerate throughout the life of the animal, and all that remain are eliminated at the time of mouse menopause, which occurs at approximately 12-14 months of age.

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