The cancer gene BRCA1, which keeps tumors in the breast and ovaries at bay by producing proteins that repair damaged DNA, may also regulate brain size. Mice carrying a mutated copy of the gene have 10-fold fewer neurons and other brain abnormalities, a new study suggests. Such dramatic effects on brain size and function are unlikely in human carriers of BRCA1 mutations, the authors of the study note, but they propose the findings could shed light on the gene's role in brain evolution.
Scientists have known for a long time that the BRCA1 gene is an important sentinel against DNA damage that can lead to ovarian and breast cancers. More than half of women with a mutated copy of the BRCA1 gene will develop breast cancer, a statistic that has led some who carry the mutation to get preventative mastectomies. But its roles outside the breast and ovaries are less clear, says Inder Verma, a geneticist and molecular biologist at the Salk Institute for Biological Studies in San Diego, California, who headed the new study. Mice bred without BRCA1 die soon after birth, so it’s clear that the gene is necessary to sustain life, but scientists are just starting to unravel its many functions, he says.
Several years ago, one of the students in Verma’s lab noticed that BRCA1 is very active in the neuroectoderm, a sliver of embryonic tissue containing neural stem cells that divide and differentiate into the brain’s vast assortment of cell types and structures. Verma and his colleagues wondered why the gene was expressed at such high levels in that region, and what would happen if it were eliminated. They created a strain of mice in which BRCA1 was knocked out only in neural stem cells. As the mice developed, Verma’s team found that the rodents’ brains were only a third of their normal size, with particularly striking reductions in brain areas involved in learning and memory. The grown mice also had a wobbly, drunken gait—a telltale symptom of ataxia, a neurological disorder that affects muscle control and balance, the researchers report online today in the Proceedings of the National Academy of Sciences.
Verma, lab member Gerald Pao, and colleagues set out to determine why deleting BRCA1 had caused such problems. Although neural stem cells were dividing at a normal rate, unusually high numbers of cells died soon after they formed, they found. The researchers also found that BRCA1 proteins were helping keep DNA from crumbling as the cells divided. Without BRCA-induced DNA repair, a molecule called ATM kinase sensed the excessive DNA breaks and activated a chemical pathway that kills off damaged cells. As a result, in mice with defective BRCA1 genes, far more cells were eliminated than would be destroyed in normal brain development. Many of the cells that did survive were malformed and disorganized, showing additional effects of defective DNA packaging, Verma says. The cellular disarray is similar to that seen in cancer, he says: Both cancer cells and the brain cells show “no orderly conduct.”
Verma is quick to point out that although there have been two case studies in which BRCA1 mutations were linked to brain abnormalities, the dramatic effects documented in the mice in the study are unlikely to occur in women with a BRCA1 mutation, who still have some functioning BRCA1, compared with the mice who had none at all.
Verma says the new data suggest that BRCA may have a role in the evolution of brain size. Genes involved in microcephaly, a condition in which patients have brains roughly the size of chimpanzee brains, directly control the levels of BRCA1 expression, he says.
Jeremy Pulvers, a molecular biologist at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, whose lab presented similar results in an earlier paper, says that the new study “provides further evidence that BRCA1 … plays a specific role in brain size regulation.” “This is important fundamental basic science about how the genome is protected in rapidly proliferating cells in the brain,” adds Huda Zoghbi, a neuroscientist at Baylor College of Medicine in Houston, Texas.