Scientists in the Human Biology Division have identified a gene in mice that is necessary for normal brain development and may contribute to the most common form of primary brain tumors in children.
Dr. Valeri Vasioukhin and colleagues have discovered that a gene known as lethal giant larvae 1, or Lgl1, plays a critical role in shaping cell behavior during embryonic brain development.
Lgl1 was first identified in the fruit fly Drosophila, where it regulates the overall directionality of a cell—a property known as cell polarity—as well as cell growth and division. The new study from the Vasioukhin lab now shows a similarly important role for Lgl1 in the mammalian brain.
Based on these results, the researchers suspect that one function of the Lgl1 gene may be to protect mammals from brain tumors. Such genes are known as tumor suppressors.
The study, led by Dr. Olga Klezovitch, a staff scientist in Vasioukhin's lab, appears in the March 1 issue of Genes and Development. Co-authors include Tania Fernandez, a technician in the Vasioukhin lab, and Dr. Stephen Tapscott, investigator in the Human Biology Division.
To gain insight into Lgl1 function in mammals, Vasioukhin and colleagues generated mice that lack the Lgl1 gene. These Lgl1-knockout mice developed normally at first, but by day 12.5 of gestation they exhibited dramatic abnormalities. A number of brain regions become expanded due to formation of multiple well-organized, flower-patterned cell groupings called neuroepithelial rosettes. Lgl1-mutant pups have a dome-shaped head, excessive fluid accumulation in parts of the brain and die within 24 hours after birth. Interestingly, the rosette structures seen in Lgl1-mutant brains resemble those seen in human patients with medulloblastoma, a type of brain tumor that arises in the rear part of the brain, and other forms of brain tumors that arise primarily in young children.
The similarities between Lgl1-knockout mice and human brain-cancer patients are particularly intriguing when considered alongside what little is known about the human version of the Lgl1 gene. Human Lgl1 resides on the short arm of chromosome 17, a region of the chromosome that is altered in half of all medulloblastoma brain tumors.
While further research is needed to delineate the role of Lgl1 in human brain cancers, Vasioukhin said that "the similarities between what is seen in the brains of the knockout mice and human primitive neuroectodermal tumors provide solid grounds for considering mammalian Lgl1 a candidate mammalian tumor-suppressor gene."
Vasioukhin's group determined that Lgl1 deficiency leads to a loss of cell polarity in neural progenitor cells—which give rise to nervous-system tissue—and that these cell also fail to differentiate into more specialized cell types. In addition, the Lgl1 defect leads to an overall increase in division of the neural progenitor cells. The researchers believe that it is this increased number of proliferating cells that gives rise to the rosette-cell masses.