Despite its importance to the continuation of species, the differentiation of primordial germ cells into functional oocytes is poorly understood. Primordial germ cells begin to differentiate into oocytes during embryonic development in the mouse. The oocytes develop in clusters called germline cysts, a conserved phase of oocyte development in both vertebrates and invertebrates. Oocytes progress through prophase I of meiosis and arrest at the diplotene stage. They then undergo primordial follicle formation during which germ cell cysts break apart into single oocytes (cyst breakdown) and granulosa cells migrate around individual oocytes to form primordial follicles. During the process of cyst breakdown, a subset of cells in each cyst die with only a third of the initial number of oocytes surviving to form primordial follicles. The mechanisms that control meiotic progression, cyst breakdown, granulosa cell recruitment and oocyte survival are not well understood. The long-term goal is to understand molecular and cellular mechanisms that regulate cyst breakdown and programmed cell death to establish the primordial follicle pool in the mouse ovary. The objective of this proposal is to understand the role of steroid hormone signaling in regulating primordial follicle formation. The central hypothesis of the proposed research is that steroid hormone signaling maintains oocytes in cysts and prevents premature progression to the diplotene stage. Work from our lab suggests steroid hormone signaling may play an important role in maintaining oocytes in cysts and controlling meiotic progression.
The specific aims of this research are to: 1) elucidate the source and molecular mechanisms of steroid hormone signaling in regulation of primordial follicle formation; and 2) identify targets downstream of steroid hormone signaling during oocyte development. These goals will be achieved through a variety of methods including immunohistochemistry, confocal microscopy, ovary organ culture, genetics, real time PCR and next generation sequencing. Research proposed in the current application is significant because it will enhance our current knowledge by elucidating the mechanisms by which cyst breakdown and associated oocyte loss are regulated. Results obtained in this grant will help improve research efforts in ovarian biology and in treatment of conditions causing female infertility such as primary ovarian insufficiency.
The pool of primordial follicles present at birth represents the total population of oocytes available to a female during her entire reproductive life. Research proposed in this application will elucidate the mechanisms regulating oocyte development. This research will make a fundamental contribution to the understanding of the establishment of the primordial follicle pool and shed light on female reproductive disorders such as primary ovarian insufficiency, reproductive lifespan, menopause and ovarian cancer.
