Week 0: Project Introduction

Hi everyone! My name is Anjali, and welcome to my first senior project blog post! Here, I’ll discuss the background of my project and what draws me to fertility-related research.

We all know about germ cells (eggs and sperm) and reproductive organs (ovaries and testes). The ovarian reserve (the egg capacity of the ovary) is established before birth and is finite. Understanding the cellular and molecular details of germ cell development will help us better understand the determinants of ovarian fertility. In my project, I seek to identify markers of germ cells that are most likely to contribute to the ovarian reserve. Primordial germ cells (PGCs), the precursors of eggs and sperm, undergo a peculiar and challenging migration during embryonic development. I will investigate whether the heterogeneity in this migration contributes to differences in the likelihood of a germ cell surviving and contributing to the ovarian reserve to help understand what eventually selects for an egg. Simultaneously, I will be trying to develop in-vitro models to help me observe this germ cell selection. 

Why does understanding ovarian fertility and fertility matter? Fertility and reproductive health define our lives in many ways—in our society, many people organize their lives around building families. My study will help identify developmental determinants that shape the size and quality of the ovarian reserve. This may lead to future interventions to help preserve and maintain fertility, giving people more autonomy and more options to build families and structure their lives without being constrained by age or work. Furthermore, menopause — the end of the ovarian fertility period and egg release — has been linked to a higher risk of coronary heart disease and osteoporosis, as decreased estrogen levels accelerate fat buildup in the arteries and bone loss. Late menopause also increases the chances of breast cancer — the most common female cancer. Thus, understanding the balance between the proliferation and differentiation of PGCs is critical to understanding the general health of women and other people with ovaries.

Since my future blogs will reference a lot about the female germ cell development process, I think it’s handy to explain it here first if you are interested in learning more about my project. Buckle in!

At E7.25 (embryonic developmental day 7.25), primordial germ cells (PGCs), stem cells that are the precursors to eggs and sperm, are specified in the proximal epiblast. 

From E9.5 to E11.5, the PGCs migrate through the hindgut epithelium toward the gonadal ridges (the developing sex organs). By E11.5, most PGCs have localized at the gonad. 

From E11.5 to E13.5, the PGCs commit to becoming female germ cells (at this stage, they are called oogonia) as a result of bone morphogenic protein (BMP) and retinoic acid (RA) signaling. During this time, the PGCs proliferate and differentiate into oogonia in cysts. 

From E13.5 to E15.5, the oogonial cysts start breaking down as the oogonia begin entering meiosis asynchronously, becoming oocytes. Complete oocyte formation involves two rounds of meiosis, but from E15.5 to E18.5, the oocytes are arrested in prophase of meiosis 1. 

At E16.5, the pachytene checkpoint (a cell cycle checkpoint) causes the oogonial cysts to break down further as it kills off DNA-damaged and genomically unstable cells. 

While the oocytes are still in meoitic arrest, the somatic cells (the non germ cells) in the ovary begin proliferating around the oocytes. These cells are known as granulosa cells, and with the layer they form around the oocyte, the full entity is called a primordial follicle. These primordial follicles are what we refer to when we say “ovarian reserve” – they have passed the necessary tests! 

During puberty, additional layers of granulosa cells surround the primordial follicle as it is selected to mature into primary, secondary, and antral follicles. During this time, the oocytes resume meiosis until metaphase 2 of meiosis 2. During ovulation, the follicle releases what is now an almost fully developed egg into the fallopian tube, and it is only after fertilization that the oocytes complete meiosis 2.

So many words! Here are some visuals I hope will help. For future reference, anything “E” indicates a timepoint during embryonic development, and anything “P” indicates a timepoint during post-natal (after birth) development. 

Source: https://europepmc.org/article/med/27329176

Source: ResearchGate