On December 20, 2013, Dr. Heng-Yu Fan’s research group published a research report entitled “CRL4 Complex Regulates Mammalian Oocyte Survival and Reprogramming by Activation of TET Proteins” in Science. In this paper, they reported the physiological and mechanical role of an E3 ubiquitin ligase CRL4VPRBP complex in oocyte maintenance and added new knowledge to female fertility as well as premature ovarian insufficiency. This work was collaborated with Dr. Qing-Yuan Sun’s team at Institute of Zoology, Chinese Academy of Sciences. Dr. Fan and Dr. Sun are the corresponding authors, and Ph. D student Chao Yu is the first author.
In female mammals, oocytes are a kind of specialized cell type. They are generated early in life before birth and entered a resting state, which forms the primordial follicle reserve containing about 100, 000 oocytes. But no new oocytes could be regenerated thereafter. ”In puberty, the oocytes of follicle reserve are gradually and continuously activated and developed to term and ovulated in the function of sexual hormone.” Dr. Heng-Yu Fan said. Usually, a woman could ovulate about 300 to 400 oocytes in her life. If all oocytes were exhausted, the menopause would come. “Clinically, premature ovarian insufficiency means the exhaustion of oocytes before the age of 40, which affects 1-2 percent of females. But the mechanisms that maintain the oocyte survival are not well elucidated.”
"To start, we first found that components of CRL4VPRBP complex are highly expressed in mouse oocytes, suggesting that oocytes might have important functions in oocytes.” Dr. Fan said. Therefore their group used gene knockout strategy to abolish the function of this complex in oocytes. The resulting mice were totally infertile while other physiological processes weren’t affected. Further experiments showed that their oocytes degenerated soon after birth and the mice exhibit premature ovarian insufficiency (POI) phenotype that reported in human patients. “These oocytes cannot develop normally after fertilization, which led to early abortion.”
Fully-grown, healthy oocytes that have the capacity to complete meiosis, be fertilized and develop after fertilization are the base requirement of female fertility. Dr. Heng-Yu Fan’s results established the essential role of CRL4VPRBP complex in oocyte survival and early embryogenesis after fertilization. And the following biochemical results elucidated the mechanical and molecular function of this complex. “The complex regulates TET proteins, a family of DNA dioxygenase responsible for DNA demethylation, to ensure the reprogramming of embryo genome after fertilization.” Dr. Fan said.
This study was supported by National development and reproduction of major scientific research projects, National Natural Science Foundation of China and Basic Scientific Research Funding of Zhejiang University Grant.
