Using an animal model system, researchers have advanced our understanding of Fragile X Syndrome by
successfully visualizing individual mutant neurons in an otherwise normal brain. They find that brain neurons that fail to express appropriate levels of Fragile X protein are structurally abnormal and make defective connections to other neurons. The work is reported by a team led by Kendal Broadie at Vanderbilt University.
Fragile X Syndrome is the most common type of inherited mental retardation. Since the early 1990's, it has been known that the disease results from the loss of a single gene and, for the last several years, that the Fragile X gene product regulates the expression of other proteins. However, the link between this molecular function and the Fragile X brain defect has remained a mystery.
Employing a fruit fly model of the disease, the researchers utilized a new technique that allows the generation of single mutant nerve cells that are marked by their expression of a glowing fluorescent protein, making these nerve cells distinctly visible in an otherwise normal brain. In their experiments, the researchers were able to observe mutant nerve cells that either completely lacked the Fragile X protein or overexpressed it, the fluorescent protein label allowing the entire architecture of these neurons to be visualized in the intact brain.
From the observations made with this approach, it became apparent that the Fragile X protein acts as a so-called "global negative regulator" of nerve cell complexity. Nerve cells lacking the protein are more complex; they exhibit more processes, more branching, and more growth. Conversely, nerve cells overexpressing the protein are simplified; they lack normal levels of processes, branching, and growth. Moreover, electron microscope imaging revealed that removal of the Fragile X protein dramatically impairs the ultrastructure of the synaptic connections that are formed by the mutant cells. Taken together, these findings suggest that Fragile X Syndrome may be caused by alteration in the growth of the brain's nerve cells and the neuronal connectivity between these cells.
Luyuan Pan, Yong Q. Zhang, Elvin Woodruff, and Kendal Broadie: "The Drosophila Fragile X Gene Negatively Regulates Neuronal Elaboration and Synaptic Differentiation"
Publishing in Current Biology, Vol. 14, Issue 20, October 26, 2004, pages 1863-1870.