We aim to elucidate the genetic programme that regulates specification of mouse primordial germ cells (PGCs), which includes active repression of the somatic programme adopted by the neighbouring cells. We discovered that the transcriptional repressor, Blimp1/Prdm1, is the key regulator of PGC specification. We are exploring the role of this and other key genes involved in PGC specification. Furthermore, Blimp1 forms a novel complex with Prmt5 arginine methylase that is apparently critical for the specification and maintenance of early PGCs, while PRMT5 itself is independently implicated in regulating pluripotency in stem cells, which underlines the relationship between germ cells and pluripotent stem cells.

Blimp1, the key determinant of germ cell specification in mice, with a SET/PR domain and five Krueppel-like zinc fingers, which bind to DNA. BLIMP1 can potentially interact with several co-repressors to repress target genes. In germ cells, BLIMP1 forms a novel complex with an arginine methylase, PRMT5.

Following PGC specification, extensive epigenetic reprogramming of the genome follows, which is an essential first step towards the eventual generation of totipotency. In particular, when PGCs migrate into developing gonads at E11.5, they undergo extensive epigenetic modifications, including genome-wide DNA demethylation, erasure of imprints and reactivation of the X chromosome. Dedifferentiation of PGCs into pluripotent EG cells also results in a similar epigenetic reprogramming event following the loss of Blimp1 (Fig 4). We are investigating the mechanism, including the identity of intrinsic factors involved in the epigenetic reprogramming of PGCs, together with the nature of the external signals that trigger it.

Our broader objectives are to develop model systems that will attempt to mimic the key aspects PGC specification and epigenetic reprogramming in vitro. The key factors and mechanisms that govern erasure of epigenetic information in PGCs could be relevant for investigations of genomic reprogramming of somatic cells towards pluripotency in vitro. This knowledge could also contribute to advances in human medicine, including the causes of cancers, as well as for the repair and rejuvenation of somatic tissues.

Role of Blimp1 in PGC specification. Shown are early embryos from E5.0 to E7.5 depicting the formation of PGCs. The proximal epiblast respond to signals from extraembryonic tissues that induce expression of fragilis in the epiblast, and of Blimp1 in the lineage restricted PGC precursors, which develop as founder PGCs and show expression of Stella.

Expression of stella-GFP at E 7.8. PGCs are detected at the base of the allantois. Stella is located within a cluster of pluripotency genes, including nanog and Gdf3 that are expressed in ES and EG cells.

Plain English:
Germ cells, the precursors of sperm and eggs, are immortal in the sense that they generate a whole organism upon fertilisation and through them provide an enduring link between all generations, while the body cells perish with each individual. We specifically aim to discover how cells, and indeed any cell, could be converted into a germ cell. Furthermore, we are investigating their unique properties, which confer the immortal state on germ cells. Detailed understanding of the mechanism involved will be valuable for the detection and eradication of immortal cancer cells. This knowledge will also be important for manipulating stem cells and adult cells for the repair and rejuvenation of diseased body tissues, and for the discovery of new therapeutic agents that can prevent or reverse the trend in ageing tissues towards debilitating diseases such as Alzheimer’s and heart disease.

Selected publications:

• Surani MA, Durcova-Hills G, Hajkova P, Hayashi K and Tee WW (2009) Germ line, stem cells and epigenetic reprogramming. Cold Spring Harb Symp Quant Biol [in press]

• Hayashi K, Lopes SM, Tang F and Surani MA (2008) Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states. Cell Stem Cell 3, 391-401

• Hajkova P, Ancelin K, Waldman T, Lacoste N, Lange UC, Cesari F, Lee C, Almouzni G, Schneider R and Surani MA (2008) Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 452, 877-881

• Surani MA, Hayashi K, and Hajkova P (2007) Genetic and epigenetic regulators of pluripotency. Cell 128, 747-762

• Hayashi K, de Sousa Lopes SM, Surani MA (2007) Germ cell specification in mice. Science 316, 394-396

Genetic regulators, expression of pluripotency genes and epigenetic modifications in nascent PGCs

During dedifferentiation of PGCs into pluripotent embryonic germ cells (EG), Blimp1 is down regulated resulting in the expression of the repressed targets of BLIMP1, and epigenetic reprogramming in EG as observed in gonadal PGCs in vivo. Prmt5 expression is maintained and may have an independent role in pluripotency.