Abstract
BackgroundFemale reproductive potential, or the ability to propagate life, is limited in mammals with the majority of oocytes lost before birth. In mice, surviving perinatal oocytes are enclosed in ovarian follicles for subsequent oocyte development and function in the adult. Before birth, fetal germ cells of both sexes develop in clusters, or germline cysts, in the undifferentiated gonad. Upon sex determination of the fetal gonad, germ cell cysts become organized into testicular or ovarian cord-like structures and begin to interact with gonadal somatic cells. Although germline cysts and testicular cords are required for spermatogenesis, the role of cyst and ovarian cord formation in mammalian oocyte development and female fertility has not been determined.ResultsHere, we examine whether intact fetal ovarian germ and somatic cell cord structures are required for oocyte development using mouse gonad re-aggregation and transplantation to disrupt gonadal organization. We observed that germ cells from disrupted female gonad prior to embryonic day e13.5 completed prophase I of meiosis but did not survive following transplantation. Furthermore, re-aggregated ovaries from e13.5 to e15.5 developed with a reduced number of oocytes. Oocyte loss occurred before follicle formation and was associated with an absence of ovarian cord structure and ovary disorganization. However, disrupted ovaries from e16.5 or later were resistant to the re-aggregation impairment and supported robust oocyte survival and development in follicles.ConclusionsThus, we demonstrate a critical window of oocyte development from e13.5 to e16.5 in the intact fetal mouse ovary, corresponding to the establishment of ovarian cord structure, which promotes oocyte interaction with neighboring ovarian somatic granulosa cells before birth and imparts oocytes with competence to survive and develop in follicles. Because germline cyst and ovarian cord structures are conserved in the human fetal ovary, the identification of genetic components and molecular mechanisms of pre-follicle stage germ and somatic cell structures may be important for understanding human female infertility. In addition, this work provides a foundation for development of a robust fetal ovarian niche and transplantation based system to direct stem cell-derived oocyte differentiation as a potential therapeutic strategy for the treatment of infertility.
Highlights
IntroductionThe ability to propagate life, is limited in mammals with the majority of oocytes lost before birth
Female reproductive potential, or the ability to propagate life, is limited in mammals with the majority of oocytes lost before birth
Intact ovarian cord formation promotes oocyte survival and development Having demonstrated that oocytes are directly impaired and lost before follicle formation following disruption of the e12.5 female genital ridge, we explored the properties of the ovary that develop on e13.5 and enable oocyte survival after re-aggregation and transplantation
Summary
The ability to propagate life, is limited in mammals with the majority of oocytes lost before birth. Upon sex determination of the fetal gonad, germ cell cysts become organized into testicular or ovarian cord-like structures and begin to interact with gonadal somatic cells. Germline cysts and testicular cords are required for spermatogenesis, the role of cyst and ovarian cord formation in mammalian oocyte development and female fertility has not been determined. Ovarian follicles, consisting of an oocyte and surrounding somatic granulosa cells, are essential for oocyte survival and maturation [1,2]; the role of prefollicle stage fetal ovarian germ and somatic cell structures in directing mammalian oocyte development has not been well defined. Oocyte clusters become organized into poorly defined ovarian, or ovigerous, cord-like structures containing oocytes and pre-granulosa somatic cells [1]. Follicle formation appears to require intricate synchronization of oocyte precursor germ cells and pre-granulosa somatic cells [12,13]
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