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Elegant switch controls transition from egg to embryo
As an egg develops in the ovary, it stockpiles mRNAs from its mother as it will not have time to create new ones during its first stages of development. Upon fertilization by a sperm, the egg recombines the DNA of its mother and father to become an embryo. Now the stockpile of maternal mRNAs go into service — for a very brief window of time — until the embryo begins transcribing its own. This transition from egg to embryo occurs very early in humans, after only two to four cell divisions. Terry Orr-Weaver PhD, studies the fruit fly, Drosophila, to watch for this moment because of its extreme significance.
In her research, Orr-Weaver and her lab determined that key to an egg to embryo transition are three molecules that form the enzyme called PNG kinase. The abbreviation stands for: PLU, PNG, and GNU — PNG. Orr-Weaver describes PLU and PNG as "tight buddies" that are always locked together, including in the mature egg. But, in the first hour of development GNU is still covered in phosphate molecules which impede its binding to PLU and PNG.
After an egg is activated through fertilization, levels of an enzyme called Cyclin B/CDK drop dramatically. Cyclin B is the cause of the extra phosphates being attached to GNU. But with its drop, GNU loses these phosphates and can now bind to PLU-PNG. Once together, the trio becomes PNG kinase and triggers the translation of maternal mRNAs into embryo mRNAs altogether. PNG kinase also triggers the break down of GNU, and GNU quickly self-destructs, ending all translation of maternal mRNAs. This elegant process, a feedback loop and the switch it controls, are described in the journal eLife.
The design of the egg to embryo transition may be telling scientists how all human cells work to affect embryo development. For example, the mRNA switch could be a model for how cells massively and globally change mRNA translation. Similar kinase activity also exists in worm early development, indicating a similar approach may be used in other organisms — including humans.
With this greater understanding of how translation is turned on and off during very early embryonic development, Orr-Weaver is intrigued that the switch may be linked to other translation machinery.
"PNG is a kinase, which means it controls what it phosphorylates. So the big question is what proteins does it phosphorylate? Finding that out is the next big phase of this project."
The oocyte-to-embryo transition involves extensive changes in mRNA translation, regulated in Drosophila by the PNG kinase complex whose activity we show here to be under precise developmental control. Despite presence of the catalytic PNG subunit and the PLU and GNU activating subunits in the mature oocyte, GNU is phosphorylated at Cyclin B/CDK1sites and unable to bind PNG and PLU. In vitro phosphorylation of GNU by CyclinB/CDK1 blocks activation of PNG. Meiotic completion promotes GNU dephosphorylation and PNG kinase activation to regulate translation. The critical regulatory effect of phosphorylation is shown by replacement in the oocyte with a phosphorylation-resistant form of GNU, which promotes PNG-GNU complex formation, elevation of Cyclin B, and meiotic defects consistent with premature PNG activation. After PNG activation GNU is destabilized, thus inactivating PNG. This short-lived burst in kinase activity links development with maternal mRNA translation and ensures irreversibility of the oocyte-to-embryo transition.
Authors: Masatoshi Hara (1,2), Boryana Petrova (1), and Terry L. Orr-Weaver (1,3,4)
1. Whitehead Institute, Cambridge MA 02142
2. Dept. of Biology, Massachusetts Institute of Technology, Cambridge MA 02142
Terry Orr-Weaver's primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also an American Cancer Society Research Professor of biology at the Massachusetts Institute of Technology.
IBu was supported by a doctoral award from Coventry University. IBr was supported by a NWO VENI (451-15-014) grant. MF was supported by Pump Prime Grant from Coventry University.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Plucking GNU out of the trio PNG/PLU/GNU creates a brief "on-off" switch
activating translation of maternal mRNAs by the new embryo at stage 11.