Germ cells are the source of totipotency, a unique state that links all generations. We are investigating the genetic programme, which regulates specification of founder primordial germ cells (PGCs), and the epigenetic programming of the lineage, which underlie the distinctive properties of mouse germ cell lineage.

Mouse germ line cycle. (a) Founder population of primordial germ cells are detected at E7.5 consisting of about 45 cells. (b) They proliferate and migrate into the developing gonads at E10.5, when a major epigenetic reprogramming event commences, and continues during gametogenesis. (c) There is also maternal inheritance of key epigenetic and totipotency factors in oocytes, which are essential for early development.

A particular focus of our work has been to elucidate the mechanism of PGC specification by using molecular analysis of single founder germ cells and their nearest somatic neighbours. This has led, amongst other things, to the identification of Blimp1, a transcriptional regulator as the key determinant of the mouse germ cell lineage. Blimp1 is first detected in a few pluripotent epiblast cells at E6.25, which marks the emergence of PGC precursors to the 40 or so founder PGCs seen at E7.25. A specific role of Blimp1 is to repress the somatic programme represented by region-specific Hox genes in founder PGCs. PGCs are highly specialised cells, but it is possible to derive pluripotent stem cells from PGCs in culture.

Extensive epigenetic programming of the genome in PGCs follows their specification, which is an essential first step towards eventual totipotency. In particular, when PGCs migrate into developing gonads at E11. 5, they undergo substantial epigenetic modifications, including genome-wide DNA demethylation, erasure of imprints and reactivation of the X chromosome. We are investigating the mechanism and identity of the intrinsic factors involved in this event, together with the nature of the external signals that trigger it.

Our broader objectives are to use our comprehensive knowledge of the mechanism of germ cell specification and properties, to elucidate mechanisms of cell fate determination generally, for example, during differentiation of pluripotent embryonic stem cells. Mechanisms that govern erasure of epigenetic information in PGCs could be extended to investigate genomic reprogramming and dedifferentiation of somatic cells when they acquire pluripotency.

Mechanism of PGC specification. The proximal epiblast cells acquire germ cell competence in response to signalling molecules, including BMP4. Some of these cells acquire PGC fate subsequently, which is associated with transcriptional repression of genes that are expressed in the neighbouring cells, including Hox genes. Several epigenetic modifiers including Ezh2, G9a and Blimp-1 probably have a critical role in this process. PGCs continue to express pluripotent-specific genes such as Oct4, and the germ cell specific gene, stella, which is the definitive marker of nascent PGCs.

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.

Recent publications:

• Surani MA, Ancelin K, Hajkova P, Lange UC, Payer B, Western P and Saitou M (2004) Mechanism of germ cell specification: A genetic programme regulating epigenetic reprogramming. Cold Spring Harbor Symposium 69 (Epigenetics), 1-9

• Ohinata Y, Payer B, O’Carroll D, Ancelin K, Ono Y, Sano M, Barton SC, Obukhanych T, Nussenzweig M, Tarakhovsky A, Saitou M, and Surani MA (2005) Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436, 207-213

• Ancelin K, Lange UC, Hajkova P, Schneider R, Bannister AJ, Kouzarides T, Surani MA (2006) Blimp 1 associates with Prm5 and directs histone arginine methylation in mouse germ cells. Nature Cell Biology 8, 623-630

• Surani MA, McLaren A (2006) Stem cells: A new route to rejuvenation. Nature 443, 284-285

Epigenetic reprogramming in PGCs. (a) PGCs expressing Stella-GFP are seen migrating into the developing gonads. (b) When PGCs enter into the developing gonads, they undergo extensive epigenetic reprogramming of the genome that includes genome-wide DNA demethylation and reactivation of the inactive X-chromosome.

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.