BAR HARBOR, Maine -- Research conducted at The Jackson Laboratory has confirmed an important role in embryonic development for the Lunatic fringe gene, part of a cell communication mechanism known as the Notch signaling pathway that is critical to the normal implementation of the body "blueprint" in mammals and other organisms.
The findings are reported in the July 23, 1998, issue of the scientific journal Nature by a team led by Dr. Thomas Gridley, Staff Scientist at The Jackson Laboratory. "Defects in Somite Formation in Lunatic fringe Deficient Mice" is co-published in Nature with a complementary research paper on Lunatic fringe by Dr. Randy Johnson and his colleagues at the University of Texas M.D. Anderson Cancer Center.
Dr. Gridley, who has conducted extensive research in mice on the Notch family of genes, describes the Notch signaling pathway as an evolutionarily conserved mechanism first studied in the fruit fly, Drosophila. Mutations in this pathway disrupt essential signaling between cells during early embryonic development that helps choreograph implementation of the segmented body plan in organisms as diverse as insects, nematodes, and mammals. In humans, Notch mutations have been implicated in cancer and in several inherited disease syndromes.
Recent studies have demonstrated that the Notch signaling pathway specifically helps regulate development of the somite, the primary unit of segmentation in mammals. Somites are present only transiently in embryos and are arranged as clusters of cells on either side of the neural tube. They form sequentially, starting at the head, and give rise to muscle, vertebrae, and skin. In adults, the influence of the primary segmentation of the embryo can be observed in the segmented pattern of the vertebrae and spinal nerves.
The Drosophila fringe gene, which encodes a secreted signaling molecule required for Notch activation during wing formation in the fruit fly, has three known homologues in mammals: Manic, Radical, and Lunatic. Lunatic fringe is the only one of the three to be expressed in the presomitic mesoderm.
In the July 23 Nature paper, Dr. Gridley and colleague Dr. Nian Zhang of The Jackson Laboratory demonstrate that mice homozygous for a targeted mutation of Lunatic fringe exhibit defects in somite formation and in establishing somite borders. The mutation affects the "polarity" of somite patterning along the anterior-posterior axis.
The researchers hypothesize that the protein encoded by Lunatic fringe and one or both of the Notch Delta-like ligands Dll1 and Dll3 -- a ligand is a molecule that binds to a receptor on the cell surface -- function together in the presomitic mesoderm to mediate the cell-cell signaling that directs populations of cells to the developing somites, and that failure of signaling mediated by these Delta homologs leads to alteration in the positioning of the somite boundaries and allocation of cells.
"These results demonstrate that Lunatic fringe encodes an essential component of the Notch signaling pathway in mice and is required for proper segmentation of mammalian embryos," Dr. Gridley says. "These studies provide another example of the conservation of developmental mechanisms in widely divergent organisms and over vast evolutionary distances."
Dr. Gridley's research at The Jackson Laboratory was supported by grants from the National Institutes of Health and from the March of Dimes Birth Defects Foundation, and by an institutional grant to The Jackson Laboratory from the National Cancer Institute.
###The Jackson Laboratory, founded in 1929, is a world leader in mammalian genetics research. With more than 850 employees, the nonprofit, independent facility has a three-fold mission: to conduct basic genetic and biomedical research, train present and future scientists, and provide genetic resources to researchers worldwide.
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