events that are under discussion.
Figure 2.2. Migration of PGSs in the human embryo.
How Do the PGCs Know Where to Go?
Just how do the PGCs find their way to the genital ridges? How do they keep from getting lost in this long and arduous journey? There is evidence that the genital ridges secrete some chemoattractant that guides the PGCs towards them. PGCs migrate by extending filopodia (very fine pseudopods) and the cells migrate between the cells in various tissues. In addition, PGCs follow extracellular matrix components that serve as "roadways" leading to the genital ridges. These roadways are lined with fibronectin. There is evidence that the integrins are involved in the migration of PGCs since mutants lacking integrins fail to migrate into the gonads. Integrins are localized to the surface of cells where they act as receptors for molecules (e.g., fibronectin) in the ECM.
Figure 2.3 presents is a theoretical demonstration of how PGCs (red) might use their surface integrins to follow an embryonic "roadway" of extracellular material to reach the genital ridges. The yellow is meant to reflect a theoretical complex of ECM components (e.g., laminin, fibronectin, collagen) rather than a single entity such as fibronectin. Cells would stay within the yellow ECM region rather than wander into adjacent regions because they would have preferential adhesiveness ("stickiness") to the yellow "roadway". The lower image in Figure 2.3 shows a primordial germ cell moving along the ECM via binding of the cell adhesion molecule integrin to fibronectin in the ECM.
Figure 2.3. The migration of PGCs. Embryonic localization as revealed by staining for alkaline phosphatase (Top image). The role of integrin and fibronectin binding in PGC migration (Bottom image).
PGC migration is also controlled by signal transduction involving TGF-beta 1 (TGFβ1) that is secreted by the genital ridge. TGFβ1, which is discussed in subsequent chapters, acts as a chemoattractant but inhibits proliferation thereby modulating the number of primary germ cells in the gonad. The topics of chemotaxis and extracellular "roadways" will be discussed in more detail in future chapters especially when we detail the migration of neural crest cells in Chapter 12.
Teratomas
In spite of all the controls that exist to ensure that PGCs successfully find their way to the genital ridges, some cells do get “lost” in non-gonadal sites. When they do, this can have serious consequences to the embryo and the individual. Lost PGCs can develop into teratomas. Teratomas are cancerous tissue masses containing a disorganized array of various differentiated cells. In fact, teratomas look like tiny disorganized embryos. As the progenitors of sperm and eggs and because they are a type of stem cell, PGCs have the potential to form many if not all cell types of the human body. Thus, teratomas can contain hair, skin, cartilage, teeth and nerves, as well as many other cell types. As a result of their "totipotent" (ability to differentiate into any cell type) nature, when they get lost and receive the wrong information from surrounding tissues, PGCs begin to differentiate into diverse cell types. Lacking the proper signals for development, they show abnormal tissue organization.
The disorganized state of the teratoma is believed to be a result of "lost" PGCs ending up in embryonic locales where they fail to get the proper embryonic signals for development. As is detailed later in this book, these signals include diffusible signaling molecules and hormones as well as specific cell-cell adhesion molecules. Since the PGCs are totipotent—they have the ability to differentiate into all of the cells of the human body—they can differentiate into many different cell types. As mentioned above, their organization is haphazard because they don't get the proper information to organize into a normal embryonic pattern. The "totipotent" nature of primordial germ cells and their ability to function properly has been shown directly by transplantation experiments. When cells from teratomas (from one genetic strain) are inserted into the inner cell mass of normal mouse embryos (from another genetic strain), mouse teratoma cells contribute normally to development. Instead of a mouse full of malignant teratomas, a normal healthy mouse is formed. Genetic analyses verified that the cells of the teratoma were present in the normal tissues. This elegant experiment verifies the totipotency of these cells and their ability to develop appropriately given the right developmental signals. While PGCs are totipotent, it is likely that most stem cells are pluripotent (i.e., can form a large number of different cell types but not all of those found in the human body. This is because such stem cells (e.g., from blood forming tissues, skin, etc.) have already embarked on a developmental pathway that limits their fate.
Germ Cell Formation in Mammals
In humans the germ cell lineage is not established in the same way as it is in lower animals. For one thing as mentioned above, "germ plasm" does not appear to exist in humans and other mammals and the germ line is not predetermined. In the rat and mouse a similar material called "nuage" does appear in the cytoplasm of presumptive germ cells prior to gastrulation but it cannot be detected before this in the egg or during cleavage. More to the point, while PGCs are derived from the posterior epiblast transplantation experiments have shown that this material is not determined early. For example, in the mouse the germ cell lineage only becomes defined around the time of gastrulation not during oogenesis or early cleavage as it does in lower animals. Grafting experiments have shown that many regions of the mouse embryo are capable of forming germ cells when they are transplanted to the extraembryonic mesoderm region of the epiblast prior to gastrulation. Based upon this research, it can be assumed that the human germ cell population arises in a similar way.
Mosaic versus Regulative Development
At this point it is important to note an important and classic aspect of development raised by this material. In many lower organisms, the development of tissues and organs is determined as early as oogenesis. If parts of the egg are removed or specific blastomeres are removed in marine invertebrates for example, specific organs may not form. This type of development is called mosaic development. The fate of most if not all cells and tissues is established when the egg is formed. The formation of germ plasm is one example of the determination factors set up in such embryos. Humans and other mammals are at the other end of the developmental scale. The formation of human tissues and organs occurs in a sequential series of steps with each step defining the next. If a part of the embryo is removed during early development, the embryo can often survive and develop normally. If two blastomeres are separated, each can form an embryo. This is called regulative development. Many animal species fall between the two ends of the spectrum of mosaic and regulative development. The important topic of determination of cells and tissues and cellular interactions (e.g., induction) that mediate the process will be covered at many times throughout this book.
BMP and DAZ Genes and Human Germ Cell Formation
Various genes and factors are important in PGC migration and differentiation (Figure 2.7). Bone morphogenetic protein (BMP; originally revealed as a factor involved in bone morphogenesis) has been proven to be critical since mice with null mutations in the gene encoding Bmp4 lack primordial germ cells. While germ-line determination is likely to differ from other animals in many specific ways, work on lower forms has guided the direction of human studies. For example, over the last few years, another gene first identified in Drosophila as being important in germ cell development has also been shown to function in germ cell formation in humans. Mutations in the human DAZ gene (Deleted in Azoospermia) and/or its homologs can result in the absence of either eggs or sperm cells. The exact role
