GAMETOGENESIS
1. The Oocyte
a. Oogenesis and maturation
Growth and differentiation of oocytes involves both cytoplasmic and nuclear (meiotic) maturation. The endocrine system is a modulator and regulator of maturation but the precise cellular, hormonal, and molecular interactions are still under intense investigation.
At the end of the migration phase about 1700 primordial germ cells populate the genital ridge of the female. Mitosis increases this number to about half a million by the end of the embryonic period; and perhaps 7 million by the end of the second trimester. Most of these rapidly degenerate, leaving about 1 million viable germ cells (most as primary oocytes) at birth. Of these, only 400-500 actually become mature ova released from follicles!
In the embryo the first meiotic prophase begins, but arrests at diplotene of first meiotic division; primary oocytes, each surrounded by a single layer of somatic follicle cells, form the primordial follicles that populate the ovary from birth until puberty. In humans, the oocyte remains arrested in meiotic prophase I until the preovulatory surge of LH at puberty at which time the cell resumes meiosis.
Meiotic maturation refers, first, to prophase I arrest during which the oocyte grows in size and the cytoplasm and nucleus undergo growth and differentiation, second, to resumption of meiosis and completion of the reduction division associated with meiotic spindle and polar body formation, and third, to release from arrest at the second meiotic metaphase and the formation of the haploid gamete after sperm activation of the oocyte.
The mechanism by which the oocyte remains arrested within the ovary until puberty and the relationship to follicular development and hormonal status of the females is another area of ongoing research. Several working hypotheses of meiotic maturation-inhibition have been suggested: 1) Maturation inhibitors within the follicle are transferred to the oocyte through gap junctions and maintain arrest until the gonadotrophins uncouple the cells. 2) Oocyte maturation depends upon acquisition of a preprogrammed meiotic competence in the oocytes which occurs independent of follicular development and gonadotrophin regulation. 3) The development of ion channels induces maturation in the oocyte.
Onset of puberty results from pituitary hormones (mainly FSH and LH) that stimulate follicular development. Each month, in rhythm with the uterine menstrual cycle, up to 12 follicles begin to mature in the ovaries. Follicle cells stop secreting oocyte maturation inhibitor (OMI) and become columnar, while the primary oocytes begin to enlarge. At this stage they are called primary follicles. Follicle cells proliferate to form a multicellular layer, the theca folliculi. This is a connective tissue capsule that separates the growing follicle from the rest of the ovarian stroma, and secretes estrogens. At the same time, the egg is secreting the zona pellucida layer around the oocyte. When the fluid-filled spaces that appear among the follicle cells coalesce into a single cavity, the antrum, the ovarian follicle is called a secondary or antral follicle. The antral cavity enlarges, pushing the oocyte to one side of the follicle, where it remains embedded in a hillock of cells, termed the cumulus oophorus. These cells are coupled to each other and to the oocyte by gap junctions. Halfway through the menstrual cycle (about 48 hours before ovulation), a surge of LH secretion from the pituitary activates one of the antral follicles to complete its maturation. The follicle cells uncouple from the oocyte, releasing it from inhibition by OMI and allowing it to complete first meiotic division to form one polar body and a secondary oocyte. The stimulated follicle rapidly swells to form a mature (or Graafian) follicle that produces a visible bulge at the ovarian surface termed the stigma. On about the 14th day of the menstrual cycle (usually less than 24 hr after the LH surge), pressure in the gel-like antral fluid causes the wall of the mature follicle and overlying ovarian epithelium to rupture, expelling the oocyte and its surrounding cells into the fimbriated funnel-like end of the oviduct. The nucleus of the secondary oocyte begins the second meiotic division, but arrests in metaphase. Only if fertilization occurs, is meiotic division completed with the formation of the second polar body and the female pronucleus. NOTE: primordial, primary and secondary follicles all contain primary oocytes, arrested in first meiotic prophase. Only the mature follicle contains a secondary oocyte, a condition that lasts only a few hours before ovulation.
The mature egg contains a large storehouse of cytoplasmic components that it has accumulated during its maturation. These components include: yolk proteins that serve as a storable supply of energy and amino acids until the embryo establishes a nutritional relationship with the mother, ribosomes and tRNA that support the rapid protein synthesis that begins soon after fertilization, maternal mRNA that provides the messages for essentially all protein synthesis through cleavage stages, and cytoplasmic determinants that direct the early development of cellular diversity. These factors are localized throughout the egg and become segregated into different blastomeres during cleavage. These components represent many of the epigenetic factors referred to in Lecture 1.
b. Summary
Embryonic period: PGCs migrate in cortex, extensive mitotic activity,
differentiation into oogonia.
Fetal period: oogonia proliferate mainly during the embryonic and early fetal periods, and all enter meiotic prophase before birth. Therefore, newborn females have only primary oocytes in their gonads.
Birth to puberty: primary oocytes arrested in first meiotic prophase.
Puberty: no further germ cell mitosis, monthly rhythm of follicle differentiation and ovulation begins, one oocyte per month; each primary oocyte forms a single mature oocyte and three polar bodies.
2. The sperm
a. Spermatogenesis and spermiogenesis
Spermatogenesis is the production of spermatids from spermatogonia. This process begins at puberty, with a pre-meiotic burst of RNA synthesis, analogous to that in oogonia. Two types of spermatogonia can be identified in humans. Type A divides by mitosis. Some of the daughter cells remain as spermatogonia and continue to divide, thus representing a stem cell population. The others convert to type B which undergo meiotic division to form haploid spermatids. Newly formed spermatids are joined in clusters by intercytoplasmic bridges resulting from incomplete cell division.
Spermiogenesis refers to the transformation of spermatids into mature spermatozoa and is often simply considered a part of spermatogenesis. This process includes three phases: degeneration and disappearance of most cytoplasmic organelles, and localization of mitochondria in the mid-piece of the forming tail; formation of an acrosomal vesicle, a specialized secretory organelle containing hydrolytic enzymes that enable the sperm to penetrate the egg's outer coat; and a period of maturation or condensation in which the DNA of the haploid nucleus becomes tightly packed into the sperm head.
Mature sperm taken directly from the seminiferous tubules of the testes are not fertile. They must undergo an activation process called capacitation before they are capable of fertilizing an egg. This process normally requires 7-8 hours exposure to the female genital tract, and results in part from enzymatic removal of glycoproteins (termed acrosomal stabilizing factors) that coat the sperm surface, and from other changes in the acrosomal cap membrane. The acrosome reaction releases enzymes, termed lysins, that disrupt the corona cells that surround the egg, and permit the sperm to penetrate the corona and reach the zona pellucida.
Results from in vitro experiments suggest sperm binding to the zona pellucida is species-specific. Sperm receptors (products of the ZP3 glycoprotein) are synthesized by growing oocytes and assembled (along with ZP1 and ZP2) into the zona pellucida of eggs that will be ovulated. The ZP3 serves as both sperm receptor and acrosome reaction inducer. Acrosome-intact sperm recognize and bind to the receptor via a specific O-linked oligosaccharide on the ZP3 that alone is responsible for recognition and binding. The ZP3 polypeptide backbone directs the sperm to undergo the acrosome reaction. Thus ZP3 serves dual functions based on its structure. The polysaccharide is located in the jelly coat and the protein component is located in the vitelline envelope. ZP3 is modified, by oligosaccharide cleavage, shortly after fertilization and sperm can no longer bind.
b. Summary
Embryonic period: PGCs migrate into medulla, mitosis, differentiate
into spermatogonia.
Fetal period: spermatogonia proliferate but become mitotically dormant
at birth.
Birth to puberty: spermatogonia differentiate into type A stem cells and
type B germ cells ready to enter meiosis.
Puberty: type A spermatogonia begin rapid proliferation, which continues throughout adult life, type B cells enter meiosis, begin RNA synthesis and formation of spermatids; each primary spermatocyte produces four mature sperm.
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