How do babies happen?

Researchers at the Technion – Israel Institute of Technology, in collaboration with researchers at Nagoya and Tokyo Universities in Japan, have uncovered a significant new function of the mammalian sperm protein IZUMO1 that may ultimately lead to more targeted diagnoses and treatment of human fertility problems, as well as enable the development of more sophisticated forms of contraception.

The study, published in The Journal of Cell Biology, was led by Technion researchers Professor Benjamin Podbilewicz and postdoctoral fellow Dr. Nicolas Brukman from the Technion’s Faculty of Biology, and Professor Tetsuya Higashiyama and Dr. Kohdai Nakajima from the Nagoya and Tokyo universities, Japan.

The research group from the Technion,R-L: Prof. Benjamin Podbilewicz, Clari Valansi, Dr. Nicolas Brukman, Xiaohui Li and Katerina Flyak

The researchers found that the protein IZUMO1, which had been discovered in 2005 by Inoue and collaborators to be critical for the binding of sex cells, also plays an essential role in fusing the cells to allow the exchange of genetic material and, ultimately, the creation of the zygote. In 2017, Podbilewicz’s lab discovered the fusogenic function of a different protein responsible for the fusion of sperm and egg cells in plants.

During mammalian fertilization,  the plasma membranes of the sex cells attach via an interaction between the sperm protein IZUMO1 and the egg protein JUNO. Once this binding has taken place, IZUMO1 works unilaterally as a fusogen to allow the  exchange and combination of the sperm’s and egg’s respective DNAs into a single nucleus. IZUMO1 is the first such protein to be designated as a fusogen in mammalian reproduction.  The present study was conducted in the lab, utilizing sperm and eggs from mice and kidney cells in culture.

Dr. Nicolas Brukman, postdoctoral fellow at Podbilewicz lab

Interestingly, the two functions of IZUMO1 – in binding and fusing – operate in a compartmentalized fashion in different regions of the protein, so that each function may potentially be isolated to address specific fertilization problems related to either realm, opening the door to more tailored or personalized fertility treatments and diagnosis.

IZUMO1’s newfound property as a fusogen may also open the door to new approaches to next-generation male oral contraceptives that temporarily disrupt the sperm protein’s binding and/or fusing abilities. This new function of IZUMO1 makes it even more suited to its name, which is taken from one of the most sacred shrines in Japan, dedicated to marriage.

A kidney cell expressing JUNO and a protein that binds DNA (green) was mixed with mouse sperm cells expressing IZUMO1 (red) and their DNA is stained in blue. The pink arrowhead points a sperm that is bound but did not fuse and the white arrowhead points a sperm fused to the cell and therefore is stained in green

Kidney cells expressing IZUMO1 and a fluorescent protein on the nucleus (magenta) are bound to a mouse oocyte expressing a fluorescent protein on the membrane (green) and a blue staining to see the DNA.

Click here for the paper in The Journal of Cell Biolog