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Primordial germ cells (PGCs) are the embryonic precursors of the adult gametes. Although restricted in developmental potency, PGCs express many of the same molecular markers as pluripotent embryonic stem (ES) cells and can give rise to embryonal carcinoma (EC) cells, the stem cells of testicular tumors, in vivo. Likewise, when exposed to specific growth factors in vitro PGCs can be converted into pluripotent embryonic germ (EG) cells. Here, we propose that genes differentially expressed between PGCs and ES cells are good candidates for regulating germline development. To identify genes important in regulating germ cell development and mammalian fertility, we performed suppression subtraction hybridization (SSH) between PGCs and ES cells whole gene set. Using this method, we identified the transcriptional coactivator/histone acetyltransferase CREB-binding protein (CBP) as being highly expressed in PGCs compared to ES cells. To elucidate the function of CBP in PGCs, we generated mice with a PGC-specific deletion of CBP. Loss of CBP in PGCs leads to increased apoptosis and subsequent reduction in PGC numbers. These data indicate an essential role for CBP in maintaining normal germ cell development.

The survival of the germline is vital to the survival of all animal species. Failure of germ cells to survive or to differentiate properly in the animal can result in reduced fertility, or in some cases, complete sterility (1). In addition, defects in germline development can predispose individuals to development of cancer. For example, loss of germ cells from the ovary can be associated with premature ovarian failure, but can also dispose affected individuals to the development of ovarian cancer (2). Similarly in the male, loss of germ cells from the developing testis can be associated with the development of testicular teratocarcinoma (3). Testicular cancer is the most common malignancy in young men with a peak incidence from 18–35 yr of age (4, 5). This contrasts with the incidence of ovarian tumors, which show a higher incidence after 50 yr of age, as is the case with most other solid tumors (6). Thus, even in otherwise healthy individuals, survival of the germline is an important feature of adult homeostasis.

Correct testicular function requires that a full complement of testicular germ cells be present in the adult testis. The germ-cell compartment of the testis is established early in embryonic development from the germline progenitor cells, termed primordial germ cells (PGCs). In mammals, the embryonic history of the germline has been well established. PGCs can be traced in the embryo by staining embryo sections for tissue nonspecific alkaline phosphatase (TNAP) and by antigenic markers recognized by rabbit polyclonal and mouse monoclonal antibodies (1–5). That these TNAP+ cells are indeed PGCs is confirmed by the fact that these cells are deficient or absent in mouse mutants that are sterile (6–9). PGCs arise outside of the gonad anlagen, and colonization of the gonad is brought about partly through the morphogenetic movements of the embryo and partly through active directed migration (2). During this period of gonad colonization the numbers of germ cells increases.