Having a healthy, functional ovary depends on its correct development during embryogenesis. In the adult, the ovary has two main functions – to produce oocytes, which are essential for reproduction, and to secrete female sex hormones such as estrogens. The primary function of estrogens is to control the development of female secondary sex characteristics and physiology. Estrogens, however, have increasingly been recognized for their importance in many other cells and tissues such as osteoblasts, chondrocytes, vascular endothelium, and aortic smooth muscle cells. Hence, pathologies that affect normal ovarian development are not only important in explaining ovarian diseases such as premature ovarian insufficiency and ovary-based infertility but are also a significant contributor to compromised bone and cardio-vasculature health; in other words, an impact that can last a lifetime. Notably, few of these pathologies have a known molecular basis; therefore, ongoing studies are necessary to shed light. Here we present what might at first blush seem like an eclectic collection of reviews related to ovarian development. Instead, it represents a range of foundational knowledge sourced from invertebrate and vertebrate species that is critical to elevate our broader understanding so that we can collectively work to translate normal into pathological processes.
Ovaries develop from the same precursors as testes, namely the genital ridges. Primordial germ cells (PGCs), the precursors of eggs and sperm, are specified outside of the developing gonads in most species and migrate towards the developing genital ridge to coalesce with the somatic cells. Depending on either genetic or environmental triggers, the genital ridges differentiate either along the male or female pathway. Historically, a lot of research has focused on the understanding of testicular development since the discovery of the Sry gene as the testis-determining gene in mammals. In recent years, however, exciting progress has been made in understanding the molecular and cellular pathways driving ovarian development. This includes not only traditional model species such as mouse and chicken, but also integral investigations and comparisons of ovarian development among many other species, including human.
In this themed issue, we wanted to bring together the most recent advance in our knowledge about ovarian development relating molecular mechanisms that drive the differentiation of PGCs into functional oocytes and their crosstalk with somatic granulosa, theca, and other stromal cells, along with how environment may influence these processes and what happens during aging in a variety of species ranging from nematodes to mammals. The issue kicks off with a review by Gregory Davis, Hayleigh Hipwell, and Peter Boag discussing key aspects of Caenorhabiditis elegans as a model system to study oogenesis. The advantages of using this nematode as a model system include a transparent body for easy visualization, a complete map of the exact lineages of every cell in the body, and a high level of conservation.
This is followed by a chapter on the development of ovaries and sex change in fish by Mateus Adolfi, Alexandra Depincé, Ming Wen, Qiaowei Pan, and Amaury Herpin. Fish are arguably the group of vertebrates with the highest variability when it comes to mechanisms to determine and even change sex. Few other vertebrates are known to have hermaphroditism, i.e., functional testicular and ovarian tissue in the same individual and can change their sex during their life, so-called sequential hermaphrodites. This includes change from female to male (protogyny), male to female (protandry), and bi-directional. Hence, any discussion about ovarian development is incomplete without including the event, leading to and during when fish change their sex.
Reptiles and amphibians are also impressive groups to study reproductive modes and sexual differentiation. The diversity in mechanisms by which ovary versus testis differentiation occurs in these species rivals that in fish and is often used to explain evolutionary branch points. Christopher Smaga, Samantha Bock, Josiah Johnson, and Benjamin Parrott present the state of knowledge regarding ovarian development in reptiles and amphibians, highlighting their use as great models to investigate not only adaptive but also disruptive embryo-environment interactions and how those mechanisms may influence reproductive strategies.
Next, Michael Clinton and Debiao Zhao present sex determination and ovarian development in birds, which have a ZZ/ZW sex determination mechanism, i.e., the female determines the sex of the offspring. Curiously, in most birds, the ovaries show a clear left-right asymmetry with only the left ovary developing and the right remaining rudimentary, which has been hypothesized to have provided an advantage to early flying birds due to a reduction in weight. This review describes the molecular mechanisms driving these developmental processes including the roles of hormones.
Finally, the last three chapters discuss different aspects of oocyte and ovarian development in mammals. First up is a review by Monica Laronda highlighting the developmental pathway of PGCs, the precursor of the gametes, into functional eggs and the factors that are essential for their proper specification, migration, differentiation, and maturation. Extensive research has been performed in mice to understand what drives these processes with the main studies described here and discussed how the knowledge we gained can help us with the understanding of human conditions.
The second chapter covering aspects of mammalian ovarian development is by Emily Frost, Emmalee Ford, Alexandra Peters, Robin Lovell-Badge, Güneş Taylor, Eileen McLaughlin, and Jessie Sutherland. Here they discuss the newest insights into the establishment and maintenance of the ovarian reserve. In contrast to males, who have spermatogonial stem cells in the testes and continuous replenishment of gametes, females are born with a finite number of oocytes, often labeled as the ovarian reserve. Our knowledge about the molecular network that underlies the formation and maintenance of the ovarian reserve has significantly increased recently through the use of the latest technologies such as single-cell RNA sequencing. The authors review and compare data from different species to draw conclusions that are important for not only understanding human reproduction but also conservation biology and agricultural settings.
The special issue concludes with a chapter written by Jesus Lopez, Gabe Hohensee, Jing Liang, Meirav Sela, Joshua Johnson, and Amanda Kallen that reviews what is known about the aging ovary. Although aging is often thought of as an event that occurs late in life, ovarian aging begins typically at mid-life or around the age of 40 in women and may occur much earlier in women suffering from premature ovarian insufficiency. Here, the authors outline key mediators related to ovarian aging, including DNA damage, mitochondrial dysfunction, among others, and highlight critical features that are often blamed for accelerated aging leading to premature depletion of the ovarian reserve. Ongoing questions are presented to encourage investigators in helping to uncover new and better targets to prevent accelerated ovarian aging.
We are very grateful to all contributors to this issue and thank each and every one for their knowledge, time, and diligence that went into writing these chapters. We also would like to extend these appreciations to the reviewers for their insightful comments and suggestions. We hope that you enjoy this special issue as much as we do and that it will provide interesting and exciting new insights into the fascinating biology of ovarian development that is essential for so many areas including reproduction, human disease, conservation, agriculture, management of pest species, just to name a few.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
No funding was received.