Dec. 7, 2000 In a new study, scientists at The Wistar Institute report the first direct evidence that RNA editing is essential to mammalian embryo development. RNA editing is a normal but not yet fully understood process in which small nucleotide changes occur after DNA has been transcribed into RNA. The process makes it possible for one gene to be translated into multiple proteins with different structures or functions.
The researchers repeatedly attempted to delete, or knock out, in mice a gene known to be involved in RNA editing called ADAR1 in order to study its function. Certain target genes in the brain are known to be subjected to RNA editing by the ADAR1 enzyme, including glutamate receptor ion channels, critical for memory formation, and serotonin receptors, which regulate emotional behaviors. The investigators expected that deletion of the ADAR1 gene would therefore lead to significant changes in brain functions.
Unexpectedly, however, they found that the knockout mouse embryos died midterm due to an inability to make mature red blood cells. At the least, the results suggest that ADAR1 and RNA editing are critical to the development of mature red blood cells, an essential step in mammalian embryo development. The new findings were published in the December 1 issue of Science.
"The inability of mice with a defective RNA editing system to make mature red blood cells is likely just the tip of the iceberg," says Wistar professor Kazuko Nishikura, Ph.D., senior author on the study. "The ADAR1 gene is expressed in many tissues throughout the body in addition to the brain and is probably involved in the RNA editing of a number of target genes that have not yet been identified."
As scientists prepare to enter the post-genomic era, the role of RNA editing in determining protein structure and function may become an increasingly important consideration in genetic research. Investigations such as Nishikura’s indicate that RNA editing is fundamental to key biological processes and point to the complexity of predicting protein structures and functions from gene sequences alone.
Before the discovery of RNA editing in mammals in the 1990s, it was believed that the path from DNA to protein was fairly straightforward: DNA in a cell’s nucleus is transcribed to RNA, and then sometimes shortened to splice out noncoding sections to form mature messenger RNA. The mature messenger RNA is transported to the cell’s cytoplasm, where translation to protein occurs.
But researchers learned that mammalian protein production can be more complicated; some RNA is edited prior to translation. Single or multiple nucleotides may change before the mature messenger RNA moves into the cytoplasm, leading ultimately to the production of a protein that does not fully reflect the original genetic instructions in the DNA. RNA editing is, in a sense, an economical system, enabling one gene to produce a number of proteins with different structures or functions. Scientists believe that the known target genes represent only a fraction of those that are subjected to RNA editing.
Nishikura and her co-investigators aimed to produce a mouse line lacking the gene ADAR1, which is part of a small gene family that produces enzymes involved in the RNA editing of a number of target genes. Midway through development, however, the mouse embryos lacking the ADAR1 gene died, which surprised the researchers; often, gene knockout mice are born alive because the mother supplies necessary biological functions to its embryos. Further study revealed that the embryos died due to an inability to produce mature red blood cells.
"We believe that when the ADAR1 gene is knocked out, the reduced or lost capacity to edit messenger RNA causes this defect in red blood cell production," Nishikura says. "Our next goal is to identify the target gene or genes that must be edited by the ADAR1 enzyme in order for red blood cell production to occur, as well as other target genes for RNA editing by this enzyme."
She adds that the ADAR1 gene knockout study will likely lead to new research aimed at discovering the mechanism for making normal red blood cells in mammalian embryos.
The study builds on earlier work by Nishikura’s research team, which was the first group to clone the ADAR1 gene in 1994.
The lead author on the study is Quinde Wang, M.D., Ph.D. The other co-authors are Jaspal Khillan, Ph.D., and Paul Gadue, B.S. Funding for the work came from the National Institutes of Health, the Human Frontier Program Organization, and the Doris Duke Charitable Foundation.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the basic mechanisms underlying major diseases, including cancer and AIDS, and to developing fundamentally new strategies to prevent or treat them. The Institute is a National Cancer Institute-designated Cancer Center — one of the nation’s first, funded continuously since 1968, and one of only 10 focused on basic research. Founded in 1892, Wistar was the first institution of its kind devoted to medical research and training in the nation.
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