Principal Investigator David Page
Germ cells, which give rise to differentiated gametes (sperm in males and eggs in females), are the ultimate expression of sexual dimorphism. Our goal is to learn how germ cells initiate the meiotic program and acquire a female or male identity (ultimately oocyte or sperm) through genetic and molecular analysis of germ cell differentiation in the mammalian ovary and testis. Starting in the late 1990's we have used the mouse as an experimental model to genetically dissect the process of meiotic initiation, which is a critical juncture in mammalian development, both female and male. Our initial genetic insight came from the discovery that the Stra8 gene is required for meiotic initiation in germ cells of fetal ovaries. Rapid progress followed, including 1) the identification of retinoic acid (RA) as an extrinsic inducer of Stra8, 2) the discovery that RA and Stra8 govern meiotic initiation in postnatal testes, and 3) the discovery that the Dazl gene encodes a meiotic competence factor, enabling fetal germ cells to respond to the RA signal, express Stra8, and enter meiosis. One of our recent findings overturned the long-held view that germ-cell sex determination is dependent on the timing of meiotic initiation. We found that Stra8-deficient female germ cells, which are blocked from initiating meiosis, still differentiate into oocytes. Our work is now focused on using new tools to expand the genetic regulatory network involved in meiotic initation
The essential function of germ cells is to carry the genome from parent to offspring, thereby providing a continuous link between generations. In order to perform this function, germ cells must complete a complex developmental program, which includes maintaining the diploid genome throughout embryogenesis, halving the genome during meiosis, and preparing the haploid genome for fertilization. Through this process, germ cells undergo extensive cellular differentiation and specialization, but they are still capable of generating a totipotent embryo at fertilization. Our recent studies have pointed to the existence of an epigenetic mechanism that might explain this unique ability of germ cells. We have found that germ cells in mice maintain a poised chromatin state, characterized by simultaneous activating and repressing histone signatures as well as silent transcription, at a subset of developmental regulatory genes. The poised state persists through multiple stages of male and female germ cell development. We postulate that maintenance of a poised chromatin state at promoters of developmental regulatory genes in germ cells plays a fundamental role in the ability of germ cells to re-establish totipotency upon fertilization.