Primordial germ cells (PGCs) are the embryonic precursors of the gametes, and are essential for continuation of generations in all eukaryotes. Using the mouse as a model system, our lab has described key points in the mechanism and regulation of mammalian PGC migration. During gastrulation, newly formed PGCs migrate through the posterior primitive streak into the hindgut endoderm. Shortly thereafter, they exit the hindgut, into the midline region of the dorsal body wall. From there, they migrate bilaterally to the genital ridges, which will become the gonads. By making movies of migratory PGCs, we observed that some germ cells fail to reach the genital ridges, but remain in midline structures including the hindgut and dorsal body wall. These ectopic PGCs rapidly fragment and disappear, suggestive of apoptotic cell death. Programmed cell death, or apoptosis, is an important mechanism during development that allows ectopic cells to be efficiently removed. All extragonadal germ cell tumors (EGCTs) occur within midline structures in humans, and it is thought that these arise from ectopic migratory PGCs that fail to undergo apoptosis. This thesis addresses two general questions.
1) What is the mechanism of removal of PGCs that fail to reach the genital ridges during migration?
2) What are the consequences of the failure of these mechanisms?
I show that PGCs are dependent upon Steel/c-Kit signaling for survival as they migrate towards the genital ridges, and that the withdrawal of Steel expression in the midline is the cause of midline germ cell death. Further, this death is dependent upon the pro-apoptotic factor, Bax, and the loss of Bax is sufficient to rescue apoptosis caused by the withdrawal of Steel. I then show that in the absence of Bax, PGCs outside the genital ridges, and which would normally die by apoptosis, instead survive and persist in the same regions that infantile EGCTs occur. Lastly, I demonstrate that the behavior of these extragonadal PGCs differs depending upon the gender of the embryo and the location in which they are found, and show a correlation between this phenomenon and the clinical presentation of the different types of EGCTs.