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Amander Clark clarka@ucla.edu
The Germ Cell Lineage
Abnormal development of the germ cell lineage is not fatal. Therefore, abnormal germ cell development is often only realized later in life where it manifests as infertility, premature ovarian failure or germ cell tumor formation. Germ cells are absolutely essential to ensure the correct passage of our DNA from one generation to the next, however despite this critical function, we understand very little about the molecular mechanisms necessary for correct germ cell development. Furthermore, most of our information comes from mouse modeling (see models), and it was only recently that a malleable cell-based model to study human germ cell formation was developed.
Germ Cell Specification Mammalian germ cells are specified in the epiblast through inductive signaling from the extraembryonic ectoderm and endoderm. This mechanism is distinct from non-mammalian model systems such as C.elegans, Drosophila, Xenopus and Xebrafish where germ cell determinants are localized to a distinct region of the oocyte cytoplasm, and are ultimately segregated to the germ cell lineage with successive cleavage divisions of the oocyte.
In mice, the inductive signaling that results in establishment of the germ cell lineage from the epiblast requires the appropriate temporal and spatial organization of the extraembryonic ectoderm, endoderm and epiblast. Therefore, for the mouse to be an appropriate model for human germ cell formation, the close apposition of these same cell lineages must also occur. However, the earliest stages of human embryo development are morphologically and structurally distinct from the mouse, particularly at the time of germ cell lineage specification. For a general review of human and mouse germ cell specification see Publications (Clark 2006)
Germ Cell Migration and Reprogramming Following specification, the germ cells relocate outside the developing embryo, and into the yolk sac (see germ cell figure). This process is hypothesized to prevent acquisition of the somatic program by the newly specified germ cells. The germ cells then subsequently migrate into the embryo (see germ cell figure), proliferating by mitosis and migrating towards the gonad. During the migration process, the germ cells reprogram by global genomic demethylation and erasure of sex-specific epigenetic marks such as imprints.
Germ Cell Colonization If the germ cells are female (XX) they migrate into the developing ovary, forming small nests of oogonia connected by intracellular bridges. The oogonia continue to proliferate before a subset undergo programmed cell death to reach a finite number of germ cells that subsequently arrest in prophase I of meiosis.
If the germ cells are (XY) they migrate into the developing testis. Similarly to females, male germ cells in the testis undergo further proliferation followed by apoptosis. Ultimately, the male germ cells undergo mitotic arrest within the seminiferous tubules.
Germ Cell Development in the Adult In order to form a haploid cell, female germ cells are recruited into folliculogenesis, a process where development of the oocyte coordinates development with the surrounding somatic cells. More than once oocyte at a time is recruited into the follicular cycle, with ultimately one dominant follicle going on to ovulation. During folliculogenesis, the oocyte completes the first meiotic cycle and at ovulation extrudes the first polar body. In addition, female-specific imprinted marks are also established during follicular development. Folliculogenesis is a continual and well-timed process in females resulting in the exhaustion of oocytes at approximately 50 years of age (menopause).
In males, germ cells exist as diploid mitotically active self-renewing spermatogonia on the basement membrane of the seminiferous tubules. Therefore, unlike females, males are able to theoretically produce a continual supply of sperm throughout a life-time. The most primitive spermatogonia are called Type A spermatogonia, and these can be subdivided into Asingle, Apaired, Aaligned. These Type A spermatogonia are referred to as the germ line stem cells. Type A spermatogonia subsequently differentiate into type B spermatogonia, which enter meiosis forming haploid spermatozoa.
Germ Cell Fertilization The only cell types in the body capable of fertilization and generation of an embryo are eggs and sperm. Following ovulation, the female germ cell (which is now called an egg) enters the female reproductive tracts surrounding by a thick glycoprotein rich layer called the zona pellucida and a layer of somatic cells called granulosa cells. It is in the ampulla region of the fallopian tubes where fertilization of the egg takes place by motile spermatozoa (sperm). Once a single sperm penetrates through to the egg, the zona pellucida subsequently becomes impermeable to additional sperm. Fusion of the sperm and egg membranes trigger the completion of meiosis by the egg and extrusion of the second polar body. The haploid DNA of the egg becomes enclosed within a female pronucleus and the male haploid DNA becomes enclosed within a male pronucleus. At this stage the female egg becomes metabolically active, and male DNA becomes decondensed and rapidly demethylated. The male and female pronuclei also shift positions in the fertilized egg so that they lie in close apposition. At fertilization, and with subsequent cleavage divisions to form an embryo, there is loss of the germ cell program, and further passive DNA demethylation and activation of the embryonic program. This forms the circle of life.
