How an RNA-binding protein tightly regulates the development of sperm

What is it about?

Mature sperm and eggs develop from dedicated adult stem cell lineages, called the male germline and female germline, respectively. Germ cell development proceeds from a stem cell stage, through a period of routine mitotic cell division (proliferation), and on through the meiotic divisions, which are unique to the germline and give rise to gametes (sperm and eggs) with the correct half-dose of chromosomes. Two critical regulatory points for the production of gametes are (1) the switch from mitosis to meiosis and (2) the proper progression through meiosis. Our previous study revealed that the YTHDC2 protein is required to help shut down the proliferation program to allow germ cells to properly enter meiosis. In this study, we developed a mouse model to knock out YTHDC2 at a particular cell stage, which revealed that YTHDC2 is also necessary to allow germ cells to progress in late meiosis, and that without YTHDC2 protein the cells quickly die and fail to make sperm. We found that YTHDC2 works together with other proteins to regulate germ cell progression primarily by binding and rapidly degrading specific, preexisting RNAs needed at prior developmental stages to allow the cells to properly progress to the next stage.

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Photo by 85GB photo on Unsplash

Photo by 85GB photo on Unsplash

Why is it important?

We have found that YTHDC2 plays an essential role at multiple stages of meiosis as male germ cells develop into sperm. These critical points, regulated by YTHDC2, must be tightly controlled to maintain gamete production and prevent the formation of germ cell tumors. YTHDC2 protein is conserved from flies to humans; therefore, the results of our studies lead to a deeper understanding of the causes of human infertility. Furthermore, as YTHDC2 has also been implicated in the development and progression of certain types of cancer, the conserved mechanisms that we have uncovered involving regulation of RNAs by YTHDC2 may also facilitate insight into its role in other diseases outside of the reproductive system.