Crucial brain development gene identified

Scientists 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 at the Fred Hutchinson Cancer Research Center have discovered that a gene known as “lethal giant larvae 1” (a.k.a. Lgl1) plays a critical role in shaping cell behavior during embryonic brain development. Lgl1 was initially identified in the fruit fly Drosophila, where it regulates cell polarity (the overall directionality of a cell) as well as cell proliferation. Dr. Vasioukhin and colleagues now show a similarly important role for Lgl1 in the mammalian brain.

To gain insight into Lgl1 function in mammals, Dr. Vasioukhin and colleagues generated mice specifically lacking the Lgl1 gene. These Lgl1-knockout mice – as they are known – developed normally at first, but by day 12.5 of gestation exhibited dramatic abnormalities. Lgl1-mutant pups have a dome-shaped head, severe hydrocephaly and die within 24 hours after birth. Internally, there is an expansion of the striatum region of the brain, along with the formation of abnormal cell groupings called rosettes.

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 primitive neuroectodermal tumors.

Dr. Vasioukhin and colleagues determined that Lgl1 deficiency leads to a loss of apical/basal polarity in neural progenitor cells, failure of these cells to differentiate into more specialized cell types, and an overall increase in proliferation by the neural progenitor cell population. The researchers believe that it is this increased number of proliferating cells that gives rise to the rosette cell masses.

The histological 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, in a region that is affected in half of all medulloblastoma brain tumors.

While further research is needed to delineate the role of Lgl1 in human brain cancer, Dr. Vasioukhin feels confident that “the morphologic and biochemical similarities between Lgl-/- and human primitive neuroectodermal tumors provide solid grounds for considering mammalian Lgl1 a candidate mammalian tumor-suppressor gene.”

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