A Japanese study has revealed a crucial role for microscopic structures within cells called "microtubules" in the process of egg growth and maturation.
Female fertility depends primarily on the growth and maturation of eggs within small, sac-like structures known as ovarian follicles.
Within these follicles are granulosa cells that nourish the egg, send chemical signals to it, and provide the structural support necessary for its proper growth. These cells are connected to the egg via very thin cellular extensions, resembling bridges or microchannels, called transzonal projections (TZPs), which penetrate the membrane surrounding the egg and physically connect it to the surrounding granulosa cells.
Scientists believed that these projections were mainly composed of a protein called actin, but the role of the microtubules within them remained unclear until now.
This is where the new study led by Professor Masamitsu Sato and Associate Professor Mika Toya from Waseda and Kyoto Universities in Japan comes in, in collaboration with researchers from Kyoto University and Azabu University, whose results were published in the scientific journal iScience.
To investigate the function of microtubules, the team used genetically modified mice that had been modified by deleting an important protein gene called Camsap3, a protein that helps stabilize microtubules inside cells.
They compared these genetically modified mice with normal mice, and conducted mating experiments, hormone-stimulated ovulation tests, detailed histological examinations, high-resolution imaging techniques, and specialized immunohistochemical staining to assess the impact of the loss of this protein on fertility, follicle development, and cell communication.
The study yielded surprising results, as the genetically modified female mice were completely sterile and unable to ovulate despite having regular, normal estrous cycles, which negates the possibility of a hormonal imbalance and points to a fundamental problem in the growth of the follicles themselves.
The growth of the follicles was disrupted during their transition from an intermediate to a more advanced stage, leading to their degeneration and death before reaching full maturity, with a sharp decrease in the number of mature follicles.
The most surprising result, made possible by ultra-high-resolution imaging techniques, was that more than 80% of the "transregional extensions" contain both microtubules and actin, a discovery that overturns the long-held scientific belief that these extensions depended almost entirely on actin.
Professor Sato explained that "this discovery highlights a much-appreciated role of microtubules in communication between the egg and granulosa cells," a role that is more important than previously thought.
It has been shown that the loss of the Camsap3 protein causes chaos in the organization of microtubules within these extensions, significantly reducing their number and even causing the disappearance of a specialized type of microtubule, which facilitates the transport of large molecules and vital organelles such as mitochondria (the cell's power plants) between cells.
As a result, communication between the granulosa cells and the egg is greatly weakened, preventing proper follicle maturation and ovulation.
Associate Professor Tuya confirmed that "the study proved that the Camsap3 protein stabilizes microtubules within the trans-regional projections, revealing the molecular mechanism by which poor communication between the egg and granulosa cells leads to infertility and follicular death."
This discovery is a game-changer in our understanding of the cellular mechanisms of female fertility, as it redefines microtubules as essential structural and functional components in transregional projections, and highlights the Camsap3 protein as a crucial regulator of reproductive function.
The results open the door to identifying new targets for diagnosing and treating infertility, and may also contribute to improving in vitro follicle culture systems used in reproductive research and assisted reproductive technologies.
The study concludes that the organization of microtubules mediated by the Camsap3 protein is a necessary component for maintaining communication between granulosa cells and the egg, for successful ovulation, and for maintaining female fertility, thus rewriting an important part of our understanding of reproductive biology.
