Mechanism of mouse germ cell specification: a genetic program regulating epigenetic reprogramming.

somatic neighbors is one of the most decisive events of early development in animals. There are two key routes to the initiation of the germ cell lineage. One is through the inheritance of preformed germ cell determinants or germ plasm as observed in Drosophila melanogaster and Caenorhabditis elegans (Eddy 1975; Wylie 1999). The other route, which is sometimes referred to as the stem cell model, occurs in the mouse, where a group of pluripotent cells are first established with seemingly equivalent potential from which both germ cells and somatic cells are derived (McLaren 1999; Saitou et al. 2003). These two modes of germ cell specification are referred to as preformation and epigenesis, respectively (Fig. 1). Although preformation is observed in most model organisms, it is apparently a less dominant mode of germ cell specification, and epigenesis may be ancestral to the Metazoa (Extavour and Akam 2003). Primordial germ cells (PGCs), the precursors of sperm and eggs, are the source of totipotency, which is a unique state generated by this lineage. Throughout the period of specification of PGCs and the extensive epigenetic reprogramming of the genome, germ cells require robust mechanisms to ensure that they do not undergo differentiation into somatic cells or revert to an overtly pluripotent state. Furthermore, as transmitters of genetic and epigenetic information to all subsequent generations, PGCs exhibit profound epigenetic reprogramming of the genome, which in mammals includes erasure and initiation of parental imprints that are responsible for the functional differences between the parental genomes during mammalian development (Surani 2001). Genetic mechanisms involved in PGC specification produce a lineage with the essential property of extensive epigenetic reprogramming of the genome that ensues after they reach developing gonads (Surani 2001; Hajkova et al. 2002; Lee et al. 2002). Thus, mechanisms that are involved in PGC specification, maintenance, and epigenetic reprogramming are of considerable general interest in the context of studies on embryonic and adult stem cells. Although specification of the germ line is one of the most crucial events of early animal development, the mechanisms involved are surprisingly not evolutionarily conserved. This is apparently necessary because of the vital differences in early development of different species (Saitou et al. 2003; Schaner et al. 2003; Blackwell 2004). Compared to D. melanogaster and C. elegans, for example, specification of germ cells in mammals is considerably delayed (McLaren 1999). This is evident since the first requirement in mammals is development of a blastocyst, and specification of PGCs occurs later after blastocyst implantation. It is the pluripotent epiblast cells of the egg cylinder of the early postimplantation embryo, which is the source of both PGCs and somatic cells, that are specified in response to signaling molecules (Lawson and Hage 1994; Lawson et al. 1999). Incidentally, the early epiblast cells are also the source of pluripotent embryonic stem (ES) cells, which also have the potential to generate both somatic and germ cells in vitro and in vivo (Hubner et al. 2003; Toyooka et al. 2003; Geijsen et al. 2004; Surani 2004). Despite the essential differences in the mechanisms of germ cell specification observed in different organisms, there are nevertheless certain underlying principles, such as the repression of the somatic program in germ cells, which may be conserved among organisms, as are some of the molecules and mechanisms for the maintenance and propagation of the germ cell lineage.