BETHESDA, Md. - Scientists in the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH), using mouse models to investigate a devastating human brain disorder, have demonstrated that reduced amounts of the gene responsible for this disorder radically disrupt very early brain development. The paper reporting the discovery is published in the August issue of Nature Genetics.
The disorder is type I lissencephaly, marked by severe mental retardation, seizures and early death. The disease's chief characteristic is a smooth brain, completely missing the usual convoluted grooves and fissures of the normal brain. It occurs in approximately one in 100,000 live births. The disorder has been attributed to abnormality or absence of a chromosome 17 gene for part of an enzyme known as platelet-activating factor acetylhydrolase, called PAFAH1B1 or LIS1.
By creating and studying laboratory mice with different defective Pafah1b1 genes, the researchers have demonstrated that this gene is important for a process of early brain development called neuronal migration. In neuronal migration, neurons born near the ventricles in the center of the brain travel outward along precise pathways to their eventual destinations in the cerebral cortex or elsewhere. In humans, it has been thought that having only one normal Pafah1b1 gene results in abnormal neuronal migration, and smooth brains seen in lissencephaly and another related disease, Miller-Dieker syndrome (MDS).
MDS has been traced to loss of the part of chromosome 17 that includes Pafah1b1 plus additional nearby genes that have not yet been identified. Like their human counterparts, mice with one normal Pafah1b1 gene display abnormal neuronal migration in several regions of the brain. In addition, when both copies of Pafah1b1 were inactivated, the resulting embryos surprisingly died soon after implantation, demonstrating that this gene is essential for normal embryonic development.
Studies on brain tissue from mice with one copy of Pafah1b1 revealed that their neurons migrated more slowly than those of normal mice. "We'll be able to study what exactly goes wrong in the brains of these mice to try to understand what role the gene plays in neuronal migration," said Anthony Wynshaw-Boris, the paper's corresponding author, and a scientist in the Genetic Disease Research Branch at NHGRI.
"If neurons don't migrate appropriately during development because the process is delayed, then the multitude of neuronal connections necessary for normal brain development aren't going to be made," Wynshaw-Boris pointed out. The scientists plan to use the mouse models to address the mechanisms by which neurons connect with each other, a process of fundamental importance to appropriate wiring of the brain for higher brain functions.
The work may also help shed light on seizures. Partial inactivation of Pafah1b1 could result in a brain that appears normal but contains small abnormal clusters of cells due to migration defects. Such clusters could serve as starting points for seizures, Wynshaw-Boris suggested.
The research was accomplished by the NHGRI team in collaboration with the laboratories of Chris McBain (National Institute of Child Health and Human Development) and Gary Clark (Baylor College of Medicine), and researchers at the University of Chicago.
NHGRI oversees the NIH's role in the Human Genome Project, an international research effort to develop tools for gene discovery.
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Last Reviewed: September 2006