X Chromosome Activity in Mouse XX Primordial Germ Cells

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Abstract
In the early epiblast of female mice, one of the two X chromosomes is randomly inactivated by a Xist-dependent mechanism, involving the recruitment of Ezh2-Eed and the subsequent trimethylation of histone 3 on lysine 27 (H3K27me3). We demonstrate that this random inactivation process applies also to the primordial germ cell (PGC) precursors, located in the proximal region of the epiblast. PGC specification occurs at about embryonic day (E)7.5, in the extraembryonic mesoderm, after which the germ cells enter the endoderm of the invaginating hindgut. As they migrate towards the site of the future gonads, the XX PGCs gradually lose the H3K27me3 accumulation on the silent X chromosome. However, using a GFP transgene inserted into the X chromosome, we observed that the XX gonadal environment (independently of the gender) is important for the substantial reactivation of the inactive X chromosome between E11.5 and E13.5, but is not required for X-chromosome reactivation during the derivation of pluripotent embryonic germ cells. We describe in detail one of the key events during female PGC development, the epigenetic reprogramming of the X chromosome, and demonstrate the role of the XX somatic genital ridge in this process. The last few years have led to striking advances in our understanding of the genesis of primordial germ cells (PGCs) and the importance of their correct epigenetic programming for the formation of functional gametes in mice. We investigated one aspect of the epigenetic programming of germ cells, the activity of the XX chromosomes in female germ cells between the formation of PGC precursors and sex determination. Random inactivation of one of the X chromosomes occurs in all cells of the embryo including the PGC precursors. This is followed by reactivation of the silent X in XX germ cells, but not in the XX somatic cells. The process of reactivation of the silent X chromosome in PGCs is initiated during their migratory journey to the genital ridges and may be cell autonomous. However, substantial X-linked gene reactivation occurs only in response to signals emanating from the somatic compartment of the XX genital ridges and is gender independent (occurring as well in sex reversed embryos).