‘Knocking Out’ Genes to Better Understand Embryo Development
UMass Amherst veterinary and animal science researchers Kim Tremblay and Jesse Mager, a wife-and-husband team nationally known for expertise in embryonic development, have each received five-year awards from the National Institutes of Health (NIH) to study distinct stages of embryo development in mice that have had essential genes knocked out. They will collaborate with Wei Cui, director of the Animal Models Core at the campus’s Institute for Applied Life Sciences.
Specifically, Mager and Tremblay, who are co-investigators on each other’s grants, have chosen to investigate a large number of lethal genes whose function is not well understood or not studied at all. These knock-out animals are produced by the Knockout Mouse Project (KOMP), part of the international mouse phenotyping consortium (IMPC), a global effort to identify the function of every protein-coding gene in the mouse genome. The genes that Mager and Tremblay study are those that, when knocked out – removed from the mouse genome – the embryo fails to develop and dies early on.
“We share every gene with the mouse, so learning about their biological function in mice will inform scientists about the underpinnings of human disease," says Tremblay.
Mager says, “We chose to study things that nobody else has, because the idea and goal of the project is not to re-do the effort but to contribute to this library of knowledge on what each and every gene does.” Mager will receive $3.1 million for his research and Tremblay will receive $2.1 million for her studies of the KOMP gene’s role in embryonic organ formation.
Mager says there is “a high correlation” between mouse and human genes. “We share every gene with the mouse, so learning about their biological function in mice will inform scientists about the underpinnings of human disease. Even though we have 30,000 genes in our genome, only about 5,000 have been studied by anyone; there are thousands that we know nothing about. This project is intended to look at genes that haven’t been studied at all in mammals.”
Tremblay adds, “Once you begin to understand the function of a new gene, you can begin to understand how those genes influence all kinds of diseases in the adult animal. We could potentially start studying those and come up with new drug therapies for human diseases.” The researchers point out that 60 to 70% of what are known as “essential genes” have diseases associated with the human version of that gene.
“We will learn a lot about basic function of these genes” over the years of planned experiments, Mager says. He points out that human diseases are due not to a totally knocked out gene, but to subtle gene changes that often lead to diminished function rather than no function.
The two each focus on different stages of an embryo’s development in the first 10 or 11 days, with Mager specializing in the very early stages, conception to about three days, and then days five, six and seven, “when the first critical decisions that an embryo makes take place.” The period correlates roughly to the first trimester of a human pregnancy, he notes.
Tremblay’s organogenesis and placentation research focuses on stages that follow, from about day eight to 10 or 11, she says, a period roughly equivalent to the end of the first and beginning of the second trimester of a human pregnancy. She notes, “Both of our expertise in these stages is part of the benefit to NIH. We are both are experts in what normal looks like and when things are not right.” The pair will use microscopy, dissection and immunohistology techniques to examine whether development is unfolding correctly in embryonic tissues. “At each stage, embryonic cells make critical and specific choices about what they should become, and we have methods to assess these decisions” Tremblay says.
Specifically related to her career work in liver organogenesis, Tremblay also hopes to identify genes that are involved in liver and gut development and function that first appear in differentiation of the placenta. She says, “I have to admit, we are both embryo geeks. Every time I open an embryo, I feel like I’m opening a present. There is something cool inside.”