3D structure of storage complex reveals how egg cells store developmental proteins

Egg cells need to store large amounts of proteins and other molecules to support the earliest stages of development. But how do they organize this supply? Egg cells have a dedicated storage system, but its precise structure has remained unclear for decades. In a recent study published in Nature, researchers from the Leung group Leung group at the Hubrecht Institute describe this structure in mouse oocytes in unprecedented detail. They show that key developmental proteins assemble into a stable complex that fills large portions of the cell. These findings offer new insight into the biology underlying infertility and developmental disorders.

Ovaries contain thousands of immature egg cells, called oocytes. During each menstrual cycle, one oocyte matures into an egg cell. If the egg cell unites with a sperm cell, the fertilized egg develops into an embryo and divides several times before it implants in the wall of the uterus. Because the embryo is not self-sufficient at this early stage, it relies on proteins and other molecules present in the egg cell that accumulated while it was a developing oocyte.

The egg cell’s storage cabinet

Because oocytes store large amounts of protein and other large molecules, they grow into one of the largest cells in the female body. Zeynep Kılıç, first author of the study, explains: “Sixty years ago, scientists discovered that oocytes contain abundant large protein structures called cytoplasmic lattices, which function like a storage cabinet for the cell. But until recently, we didn’t know exactly what they’re made of or how they’re organized.” The stored proteins are crucial for embryonic development: women with mutations that affect the cytoplasmic lattice often experience fertility problems.

To study how this storage system works, the team collaborated with Willem Noteborn from the Netherlands Centre for Electron Nanoscopy. They visualized cytoplasmic lattices at extremely high resolution, almost at the level of individual atoms, using cryo-electron microscopy. In this technique, researchers flash-freeze proteins to preserve their shape, then capture thousands of images with an electron microscope and combine them to reconstruct a detailed 3D model of the protein structure. The team also worked with the Proteomics team of the Centre for Molecular Medicine at UMC Utrecht to confirm these findings. Using mass spectrometry, they showed that the proteins identified in the cryo-EM reconstruction are highly abundant in oocytes.

Safe storage

The team found that the cytoplasmic lattice is a large protein complex made up of at least 13 different proteins, many of which are themselves essential for embryonic development. These proteins assemble into a stable, space-efficient structure that keeps them inactive until they are needed, like a storage cabinet that holds its contents safely out of use. Remarkably, the cell builds this cabinet out of the stored proteins themselves. This controlled storage is important: if these proteins were freely available, they could disrupt processes inside the egg cell.

Tubulin, for example, helps build the cell’s internal skeleton and transport materials across the cell, but too much free tubulin can disrupt these processes and become toxic. “The amount of free tubulin is always strictly regulated in the cell”, Kılıç explains. “By storing it in the complex, the cell can circumvent feedback mechanisms that are normally needed to maintain precise tubulin levels.” Similarly, proteins that break down other proteins, and epigenetic 'master regulators' such as UHRF1, which ensures DNA instructions are copied correctly, are safely stored in the complex until they are needed for the transition from oocyte to embryo.

Why it matters for fertility

These findings provide new insight into how egg cells store the materials needed to support early development. Although the work was conducted on mouse oocytes, human oocytes also contain most components of cytoplasmic lattices. This helps explain why mutations in genes that code for these components can lead to infertility and developmental defects. Current reproductive treatments such as in vitro fertilization (IVF) are often ineffective in these cases, highlighting the need for a better understanding of the underlying biology. This study may therefore point to new targets for future therapies.

About Miguel Leung

Miguel Leung is group leader at the Hubrecht Institute

About the Hubrecht Institute

The Hubrecht Institute is a research institute focused on molecular and developmental biology. Because of the dynamic character of the research, the institute has a variable number of research groups, around 20, that do fundamental, multidisciplinary research on healthy and diseased cells, tissues and organisms. The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), situated on Utrecht Science Park. Since 2008, the institute is affiliated with the UMC Utrecht, advancing the translation of research to the clinic. The Hubrecht Institute has a partnership with the European Molecular Biology Laboratory (EMBL). For more information, visit www.hubrecht.eu.