Semaphorin 3E Emerges as a Key Factor in Female Reproduction

Cornell researchers have identified a new cell signaling pathway involved in ovulation. This discovery could inform future studies on infertility, contraception, and ovarian diseases.

Semaphorin proteins are known to play roles in the vascular, nervous, and immune systems, as well as in cancer development. A study published on May 20, 2025, in Advanced Science reports that semaphorin 3E (Sema3E) also contributes to ovulation in mice. The paper was co-authored by ten researchers from Cornell and two colleagues from Baylor College of Medicine.

The study’s first author is Hanxue Zhang, a postdoctoral associate in the lab of Yi Athena Ren, assistant professor of animal science in the College of Agriculture and Life Sciences.

Female reproductive tissues, such as the uterus and the ovary, are unique: No other tissue in adult life goes through a similar cycle of drastic construction and deconstruction – every month in women and every four days in mice. We wanted to understand how different types of cells in the ovary communicate and coordinate with each other to enable such changes under the control of reproductive hormones.

Athena Ren, Assistant Professor, College of Agriculture and Life Sciences, Cornell University

A fully developed ovarian follicle releases an egg during ovulation. Before this happens, the inside of the follicle is one of the few places in the body without a direct blood supply. Other examples include the tubules inside the testes and the cornea of the eye.

According to Ren, the follicle essentially “creates a wound” on the surface of the ovary to release the egg. After the egg is discharged, the follicle begins producing progesterone and forming a network of blood vessels to support a possible pregnancy.

Ren added, “So before ovulation, there is no vasculature, and then once the egg is released, we see one of the highest densities of vasculature in the body, comparable to that in the most aggressive tumors. And all of this happens within 24 to 48 hours in mice. We want to understand what enables this switch.”

Zhang, Ren, and their colleagues found that altering Sema3E in mice disrupted the vascular remodeling needed for pregnancy. It also interfered with ovulation. Blocking the protein reduced the expression of genes involved in several biological processes required for ovulation.

This discovery opens new research directions. Animal scientists may study the Sema3E pathway to improve reproductive efficiency in dairy cows. Human health researchers might explore its potential for developing contraceptives or treating infertility.

Ren further added, “Because reproductive hormones act on other tissues in the body, discoveries in ovarian function could also translate to other biological processes, such as how hormones impact cardiovascular health and tumor development. We have this whole world to explore.”