May Be Cause Of Neural Tube Defects
"The more we know about how this process of neural tube closure works, the better we will be able to attack these defects," says Wallingford, an assistant professor of molecular cell and developmental biology and a member of the College of Natural Sciences' Institute for Cellular and Molecular Biology.
Wallingford conducted the study on frog embryos, which develop similarly to human embryos, while at the University of California, Berkeley. He studied the frogs with colleagues from Harvard Medical School and the University of Pittsburgh who are co-authors on the paper about this research in the Dec. 16 2003 issue of Current Biology.
Spina bifida occurs in about one in 2,000 births when the bottom end of the neural tube fails to seal. The bones of the spine (vertebrae) in the unsealed area fail to develop, and the spinal cord remains open and continuous with the skin of the back. When the unsealed area is small, the defect is minor, but leg paralysis and lack of bladder and bowel control occur in more severe cases. If the top end of the neural tube fails to close instead, anencephaly develops, in which developing babies that survive until birth often die within hours due to an underdeveloped brain and incomplete skull.
Mice, often used to model human diseases, have multiple genes identified as being involved in nervous system development. But their use is limited in studying the role of developmental genes since their embryos lie hidden within the uterus where their effects are difficult to visualize. To learn more, Wallingford and his colleagues focused on the African clawed frog, Xenopus leavis, whose large embryos develop outside the body and undergo neural tube closure like mice, humans and other vertebrates.
In Xenopus embryos at the earliest stages of development, the presence of shroom caused cells of the neural tube to constrict, or shrink, on the side of the cells facing inside the tube. That shrinkage must occur before neural plate folding can occur. When shroom function was inhibited in frog embryos, constriction didn't occur, verifying the gene's role in producing the shape change.
The protein produced from the shroom gene is known to attach to the molecules that form rope-like filaments inside cells that regulate their shape. The filaments are composed of the protein actin, which the researchers found became more concentrated at the side of the neural tube cells before constriction.
"We think that the shroom protein is going to be very directly involved in organizing those filaments to change the shape of the cell," Wallingford says.
He will study this organization in frog embryos using fluorescent imaging methods that allow the interaction of different proteins inside neural tube cells to be visualized, and by making time-lapsed videos of developing embryos.
"With these approaches, we hope to find out which proteins interact with the shroom protein to influence later steps in neural tube closure," Wallingford says.