Cortical tension, polarization and developmental potential of mammalian oocytes – CoPOcyte

Cell mechanical properties regulate various biological processes, including proliferation, differentiation, migration and adhesion. Therefore, their deregulation is involved in several human pathologies including cancer and aging. Oocytes are large cells that do not proliferate, differentiate, migrate or adhere. However, the regulation of their mechanical properties is essential to generate oocytes with an optimal developmental potential in order to produce a healthy embryo after fertilization. Strikingly, mechanical defects are rather frequent in mammalian oocytes. In particular, too stiff human oocytes show no major morphological alterations that could be assessed by simple visual inspection in reproductive medicine, but produce embryos that stop developing after fertilization for unknown reasons. The “CoPOcyte” project aims to understand how increased cortical tension reduces the developmental potential of mammalian oocytes.

Given the difficulty of performing exploratory studies on human oocytes, we will address our question in mice, before returning to human. We have developed a tool to stiffen mouse oocytes by exploiting the natural actomyosin variability of the oocyte cortex. Our preliminary results show a novel phenotype: too stiff oocytes spontaneously polarize, accumulating actomyosin in a cortical region early after entry into first oocyte division (meiosis I), while polarity is normally established hours later at the end of meiosis I in mammals.

Interestingly, several types of somatic cells spontaneously polarize when experiencing excessive cortical tension, regulating their migration mode. However, oocytes are non-motile cells so it is unlikely that the cellular effect of a spontaneous polarization is on the overall movement of the cell. Our hypothesis, supported by preliminary data, is that spontaneous oocyte polarization translates into aberrant movements within the cell, affecting cytoplasm organization including spindle and organelles, decreasing oocyte developmental potential.

Our project will test this hypothesis, using a combination of state-of-the-art approaches in cell biology, biophysics, theoretical modeling, and artificial intelligence, made possible by the high degree of complementarity of our unique consortium, composed of experts in cell biology (Terret team), biophysics (Campillo team) and medicine (Labrune team).
- First, we will characterize the mechanisms underlying precocious oocyte polarization induced by excessive cortex tension in mice.
- Then, we will explore the functional consequences of precocious oocyte polarization on oocyte and early embryo development in mice.
- Lastly, we will determine whether our findings are conserved in human oocytes by quantifying if human oocytes with increased cortex tension also precociously polarize as in the mouse, and assess the consequences.

We expect to identify a novel cellular mechanism underlying developmental failure in mammalian oocytes and apply our results to better understand the origins of infertility in humans.