Journal
EMBO JOURNAL
Volume 36, Issue 13, Pages 1888-1907Publisher
WILEY
DOI: 10.15252/embj.201695862
Keywords
cAMP signaling; epigenetic reprogramming; in vitro expansion; PGC-like cells; primordial germ cells
Categories
Funding
- Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan
- JSPS [JP24680045, JP15H05636, JP16H04720, JP16H01216, JP25112010]
- JST-ERATO [JPMJER1104]
- Grants-in-Aid for Scientific Research [16H01216, 25112010, 15H05636, 16H04720, 21249013] Funding Source: KAKEN
Ask authors/readers for more resources
The expansion of primordial germ cells (PGCs), the precursors for the oocytes and spermatozoa, is a key challenge in reproductive biology/medicine. Using a chemical screening exploiting PGC-like cells (PGCLCs) induced from mouse embryonic stem cells (ESCs), we here identify key signaling pathways critical for PGCLC proliferation. We show that the combinatorial application of Forskolin and Rolipram, which stimulate cAMP signaling via different mechanisms, expands PGCLCs up to similar to 50-fold in culture. The expanded PGCLCs maintain robust capacity for spermatogenesis, rescuing the fertility of infertile mice. Strikingly, during expansion, PGCLCs comprehensively erase their DNA methylome, including parental imprints, in a manner that precisely recapitulates genome-wide DNA demethylation in gonadal germ cells, while essentially maintaining their identity as sexually uncommitted PGCs, apparently through appropriate histone modifications. By establishing a paradigm for PGCLC expansion, our system reconstitutes the epigenetic blank slate of the germ line, an immediate precursory state for sexually dimorphic differentiation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available