June 22, 1999 UMass scientist's "knock-out mice" were part of the process
AMHERST, Mass. -- A team of scientists, including University of Massachusetts geneticist Deborah J. Good, has identified a gene which appears to be critical during embryonic development. The gene, called SIL, governs formation of the left-right body axis, and is believed to be important in the correct placement of organs such as the heart within the developing organism, according to researchers. The team, headed by Shai Izraeli of the National Cancer Institute, reports its findings in the June 17 issue of the journal Nature. The team includes colleagues from the National Cancer Institute, and the National Institute of Allergy and Infectious Diseases, and was funded by the National Institutes of Health.
Good specializes in determining the functions of genes by deleting them from mice using recombinant DNA methods. She then monitors the mice closely to determine the effects of the deletions. The mice are called "knock-out" mice, because specific genes have been knocked out. In this research project, conducted while she was a researcher at the National Institutes of Health, Good worked with senior researcher Izraeli, and high-school student Paul Thomas, who recently graduated from Wake Forest University. The three began with mouse embryonic stem cells, the primordial cells capable of developing into any part of the body. The scientists then used an electric current to insert a piece of DNA into those embryonic stem cells. The added portion of DNA integrated with the cells' own genetic coding, causing the loss of the SIL gene. The stem cells were then injected into normal mouse embryos and the resulting offspring were used to breed SIL-knock-out mice.
The resulting embryos, which lacked the SIL gene, died in utero and showed striking developmental abnormalities, Good said. The cardiac tube, which is the precursor of the heart, looped randomly rather than to the right. The cardiac tube must loop to the right to form the left and right chambers of the heart. The neural tube, which eventually becomes the central nervous system, including the brain and spinal cord, failed to close properly, a defect which is analogous to spina bifida in human beings. The affected animals also showed changes in other genes, leading scientists to theorize that SIL is responsible for guiding these other "downstream" genes to form the body axis as an organism develops. SIL is a gene expressed in proliferating cells, which would explain why it is crucial during embryonic development, when an organism's cells are dividing rapidly to form various parts of the body, Good said.
"SIL is incredibly important for asymmetrical left-right body axis development," she said. "You need to have the heart loop to the right during development. If you don't have SIL, that doesn't happen." In humans, a flawed or absent SIL gene could result in midline abnormalities, or early embryo loss, scientists say.
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