Terry Orr-Weaver, Ph.D., from the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology (MIT), was the first presenter in the 2016 NIEHS Distinguished Lecture Seminar Series. Her Jan. 21 talk was titled “Coordination of Meiosis and mRNA Translation for the Oocyte-to-Embryo Transition.” Orr-Weaver was welcomed and introduced by Carmen Williams, M.D., Ph.D., head of the NIEHS Reproductive Medicine Group.
Williams listed some of Orr-Weaver’s exceptional accomplishments, including fellow of the American Association for the Advancement of Science and the American Academy of Microbiology, and member of the National Academy of Sciences. In addition, she is an American Cancer Society Research Professor and has received the Federation of American Societies for Experimental Biology Excellence in Science Award.
The transition of oocytes into eggs is "one of the most remarkable transitions in all of biology,” Orr-Weaver said. Oocytes are female germ cells that mature into eggs through the cell division process of meiosis, which reduces the chromosome count by half. She discussed studies that shed light on links between defects in this important transition and human diseases, such as cancer and birth defects.
Oocyte maturation and egg activation
Orr-Weaver said that two key steps in the transition of oocytes into embryos are oocyte maturation, followed by egg activation. According to Orr-Weaver, egg activation is the set of events that cause completion of meiosis, restore totipotency, which is the ability of the cell to differentiate into all cell types, and allow the egg to be fertilized and enter mitosis, or normal cell division. In nearly all animals, the transition from oocyte to embryo marks the beginning of development, and more importantly, occurs in the absence of DNA transcription.
Her lab has found that the best model system for studying the changes that accompany oocyte-to-embryo transition is the fruit fly, or Drosophila. “In Drosophila, oocyte maturation and egg activation events occur at precise points in oocyte development and are morphologically distinct,” said Orr-Weaver. This allows researchers to isolate mature oocytes and activated eggs for further study. More importantly, egg activation can be separated from fertilization without impact from expression of genes in the fertilized egg.
Translational changes are key
Translation is the process by which messenger RNA turn genes into proteins. Studies by the Orr-Weaver laboratory and their collaborators reveal that translation, as opposed to transcription, is remarkably important in the earliest stages of development.
“We think so much about how gene expression can be regulated at the level of transcription, but these really dramatic developmental changes, by necessity, must be controlled by changes in translation and in protein stability,” she said.
PNG kinase complex regulates translation
In additional genetic studies, the Orr-Weaver lab identified a novel protein complex called PAN GU (PNG) kinase. According to Orr-Weaver, PNG kinase is composed of three subunits — PNG, PLU, and GNU. The PNG kinase complex is a major translational regulator at egg activation.
A translational repressor called trailer hitch (TRAL), which is present in both yeast and humans, is a critical target of the PNG kinase complex. Orr-Weaver suggested that upon phosphorylation, TRAL loses its ability to repress translation. This, in turn, leads to a burst of regulation of maternal mRNA translation.
Following the lecture, NIEHS trainees had the opportunity to have lunch with Orr-Weaver. This enabled fellows to learn more about her research and to discuss scientific and career development issues.
(Tara Ann Cartwright, Ph.D., is a former postdoctoral fellow in the NIEHS Intracellular Regulation Group).