Genetics of Ovarian Failure and Development

Aleksandar Rajkovic, M.D., Ph.D.

The ovary has been an important focus of medical and scientific investigations since antiquity. The first discoverers of the ovaries were likely farmers, who used spaying to control sexual appetite and to increase the size and fatness of animals. Scientists from ancient times such as Aristotle and Galen noted the existence of ovaries, but it was with the emergence of interest in anatomy in the 14th century and subsequent Age of Reason and Enlightenment beginning in the 17th century that ovaries received additional attention from Vesalius, Fallopius, Coiter, Fabricius, Harvey, Stensen, Leeuwenhoek, and many others who described the structure of the ovary, discovered germ cells, and began to study ovarian function in the context of reproduction. The study of the ovary evolved naturally from speculation about its function, to detailed examination of the anatomy, histology, physiology, and genetics. Physicians and scientists of every era were aided by political, social, and technological changes that allowed them to ask and answer questions with the tools available at a particular time point.

We currently are in an era in which molecular biology and genetics give us an even greater insight into the complex mechanisms that regulate ovarian function. Large-scale sequencing of many animal and human genomes, and generation of databases with sequenced transcriptomes from a wide variety of cell types and tissues, continue to provide novel molecular reagents, the critical roles of which in ovarian function would otherwise have been left undiscovered. Mouse knockout technologies are invaluable to determine functions and physiological roles of genes in ovarian biology. For cell types that lack cell lines, such as oocytes, in vivo mouse models are essential to deduce function. Currently, there are more than 200 animal models with reproductive defects, and it is likely that these represent only a fraction of the genes critical in ovarian biology. Our understanding of the genetic anatomy of the ovarian development, folliculogenesis, and ovarian pathology augments daily. Several searchable Internet-based databases are available publicly for those interested in genes that affect ovarian function. Useful Web sites include The Jackson Laboratories (http://www.jax.org), the Ovarian Kaleidoscope Database (http://ovary.stanford.edu), and The National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov).

The ovary is a unique organ composed of both somatic and germ cells, and regulated both internally and centrally by the hypothalamus and pituitary. Mutations in KAL1, FGFR1, and GNRHR cause ovarian failure in a subset of women with hypogonadotropic hypogonadism. Ovarian follicles, in turn, are the functional units of the ovary and contain a single oocyte surrounded by companion somatic granulosa and theca cells. The interactions between the soma and the germline are essential for the development of the ovary and eventually for ovulation. The inflammatory-like genes identified in the process of ovulation may represent the connection often observed between infertility and autoimmune disorders. Signaling pathways, such as those that involve members of the transforming growth factor beta superfamily, are important not only for the proliferation and differentiation of somatic cells that surround the oocytes, but also play important functions in ovarian tumorigenesis. We know that many genes necessary for early embryogenesis are transcribed and translated in the ovary. Such genes, called maternal effect genes, may be responsible for some cases of infertility observed as failed early embryonic development during in vitro fertilization. Pluripotent genes, such as GCNF, POU5F1, and SALL4 are also transcribed in the ovary and it is likely, although yet unproven, that they may contribute to the totipotentiality of the egg. Therefore, genetics of ovarian development, and specifically oogenesis, will provide more insight into the genetic mechanisms of pluripotency and nuclear reprogramming.

During the past decade, we have learned much more about genes preferentially expressed in the ovary, such as zona pellucida genes; ZP1, ZP2, and ZP3, growth differentiation factor 9 (GDF9), factor in the germline alpha (FIGLA), oogenesis homeobox (NOBOX), and (FOXL2). Genes such as FOXL2 play important functions in syndromic ovarian failure, and it is likely that other genes preferentially expressed in the ovary are involved in nonsyndromic ovarian failure. Oocyte-specific genes are also attractive pharmaceutical targets to control fertility. In addition, the role of sex chromosome in ovarian development and failure has gained from discoveries that two X chromosome genes, POF1B and BMP15, are important for ovarian function, and future delineation of X chromosome regions critical for fertility and their interactions with autosomes will yield additional insights into the genetics of ovarian failure. The burgeoning field of tissue engineering will help us to grow ovaries in vitro, and enable maturation of oocytes from primordial stages with higher efficiency. Of course, the discovery of novel and additional ovarian factors necessary for successful bioengineering will come largely from functional analysis of the ovarian transcriptome.

The genetic knowledge of ovarian development and failure is incomplete. It is hoped that in the future, we will not only catalog, but also apply our knowledge of ovarian genetic pathways to generate germ cells in vitro, to help preserve and mature follicles from children and women undergoing ablative chemotherapy, to build ovaries that resist tumors, and provide new targets to regulate human fertility. In this issue of Seminars in Reproductive Medicine, the leaders in the area of ovarian development and failure present our current understanding and give readers a glimpse of future developments.