Germ cell specification in mice: signaling, transcription regulation, and epigenetic consequences

Abstract

The specification of germ cell fate in development initiates mechanisms essential for the perpetuation of genetic information across the generations. Recent studies in mice have shown that germ cell specification requires at least three key molecular/cellular events: repression of the somatic program, re-acquisition of potential pluripotency, and an ensuing genome-wide epigenetic reprogramming. Moreover, a signaling and transcriptional principle governing these processes has been identified, raising the possibility of inducing the germ cell fate precisely from pluripotent stem cells in culture. These advances will in turn serve as a basis to explore the mechanism of germ cell specification in other mammals, including humans. The recapitulation of germ cell development in humans in culture will provide unprecedented opportunities to understand the basis of the propagation of our genome, both under normal and diseased conditions.

Primordial Germ Cells in Mice

“…BMP2 expressed in the proximal VE enhances the same signaling pathway, ensuring that the highest levels of BMP signaling occur in the most proximal epiblast. These findings are consistent with the previous observations that PGC specification has been shown to depend on the dosage of BMP signaling and the level of Blimp1 induction (Lawson et al 1999;Ohinata et al 2005;Vincent et al 2005), and that mutants for Bmp4, Bmp8b, Bmp2, Smad1, Smad4, Smad5, and Alk2 lack or have reduced numbers of AP-positive PGCs (Table 1) (Zhao 2003;Saitou and Yamaji 2010). The induction of Blimp1 expression in the posterior side of the embryo is explained by the inhibition of BMP signaling in the anterior epiblast by antagonist factors (e.g., LEFTY1 against NODAL, DKK1 against WNT, and Cerberus-like [CER1] against BMP, etc.)…”

“…Generally, the germ cell lineage is set aside from the somatic lineages early in development, either through localized maternal determinants (most typically referred to as germ plasm) or induction from pluripotent embryonic cells (Box 1). In many animals, primordial germ cells (PGCs) are the first germline cell population (Saitou and Yamaji 2010), which colonize the developing gonads by active migration (Richardson and Lehmann 2010). In the gonads, PGCs initiate differentiation either toward a spermatogenic (male) or an oogenic (female) pathway.…”

synMuv B proteins antagonize germline fate in the intestine and ensure C. elegans survival

“…The single-cell embryo has a number of attributes of the germ line, including an inherited chromatin state compatible with gene expression patterns in germ cells. In mammals, erasure of germline character is one of the first steps in embryogenesis; primordial germ cells are newly induced later in development (for a review, see Saitou and Yamaji, 2010). In Caenorhabditis elegans and Drosophila, germ cells are segregated away from somatic cells very early in development and the erasure of germline characteristics in the soma appears to be more gradual (for a review, see Nakamura and Seydoux, 2008).…”

The REV7 Subunit of DNA Polymerase ζ Is Essential for Primordial Germ Cell Maintenance in the Mouse

“…Many genes involved in the regulation of male and female reproduction have been identified in mice, and some genetic causes for male and female infertility have been identified in humans, including chromosomal aberrations and genetic alterations of genes involved in sex determination, endocrinopathies, and sperm production (41,42). However, many cases are still diagnosed with idiopathic infertility, and most of these cases are thought to have undiscovered genetic and epigenetic alterations.…”