Germ cells have the unique property of being dispensable for survival of the individual yet essential for the species. The germline is established during early development as a small population of primordial germ cells (PGCs) that give rise to the adult gametes following sex differentiation during late fetal life. This segregation from somatic lineages for all but the very first cell divisions in the embryo places an evolutionary premium on the germline. Study of PGC development will yield insights into the fundamental mechanisms of pluripotency as well as cell fate decisions, migration, and natural selection. Current projects include:
The selection or elimination of germ cells during development. A small number of primordial germ cells established during the first week of mouse development supply all of the eggs or sperm for the reproductive lifespan. This process appears to be surprisingly inefficient, with germ cells lost at multiple steps: some fail to migrate through the embryo, some proliferate less, and many are eliminated by programmed cell death. We are studying the determinants of germ cell fate during development. Our finding that the proliferation of migrating primordial germ cells is regulated by their immediate neighborhood indicates that the earlier or faster migrators contribute more substantially to the population of germ cells that end up on the gonad (Cantu et al, J. Cell Biol 2016). We are using lineage-tracing approaches to understand the clonal dynamics of primordial germ cells as they relate to behaviors such as migration, proliferation and apoptosis. At left, germ cells in the mouse fetal testes during scheduled apoptosis (pink cells) are clonally labeled (red, orange and cyan). Understanding the basis of success or failure of nascent germ cells and the relationship to quality of the adult gamete (egg or sperm) has potential implications for the origin of birth defects, infertility, and for the increasingly realistic prospect of growing gametes in a dish.
Determinants of the ovarian reserve. A woman’s reproductive lifespan is determined by the number of non-growing eggs in her ovary as well as the rate of loss during growth. The factors underlying the establishment of this reserve during fetal life as well as its maintenance during aging are poorly understood. A critical social and health issue is predicting a woman’s remaining period of fertility, but current practices measure only maturing eggs rather than the most critical reserve population. We are using mouse genetics and imaging approaches to understand how the development of oocytes in the fetus affects the size of the ovarian reserve as well as the competence of the eggs to produce embryos. At left, non-growing and early growing oocytes in a newborn mouse ovary are marked in red. Our long-term goal is to identify markers of the ovarian reserve as well as to therapeutic targets. Decelerating the loss of the ovarian reserve would prolong reproductive lifespan, particularly for patients with infertility due to primary ovarian insufficiency, however delaying menopause would potentially benefit women’s health by reducing the risk of cardiovascular, neurologic and metabolic disease.
Quantitative imaging and mathematical modeling of development. We develop tools for the study of germ cells in the embryo and postnatal gonad. We established a method to identify and count primordial and growing follicles in the intact mouse ovary by 3D imaging (Faire et al, Dev Biol 2015). We recently extended this approach to the mouse uterus to study the process of embryo implantation. This revealed that the establishment of pregnancy coincides with dynamic changes in the topology of the uterine lining and gland organization (Arora et al, Development 2016). At left, the structure of the uterine glands (multiple colors) around the implanting embryo (red ring) is shown at 4 days of mouse pregnancy.
Epigenetics and Environment in germ cell development. Distinct from changes to the genetic code, epigenetic mechanisms are important for coordinating rapid cell fate changes, particularly in periods of transcriptional quiescence (such as in early PGCs) or when cell division is not an option (such as in the oocyte). With UCSF collaborator Robert Blelloch, we found that two micro-RNAs work antagonistically to regulate the germline-somatic decision in human embryonic stem cells (Tran et al, Stem Cells 2016). As germ cell development also involves resetting of epigenetic marks as a way to wipe the slate clean for the next generation, interference with this process can potentially wield effects across generations. A current project in the lab concerns the effects of common chemicals on developing germ cells and their ‘memories’ of exposures.