BRCA1, the well known cancer gene that keeps tumors in the breast and ovaries at bay by making proteins that repair damaged DNA, may also regulate brain size. A study done on mice who carry a mutated copy of the gene have 10-fold fewer neurons along with other brain abnormalities. According to researchers, such dramatic effects on brain size and function are unlikely in human carriers of BRCA1 mutations, however they suggest the findings may shed some light on the gene’s role in evolution of the brain.
Greater than 50 percent of women with a mutated copy of BRCA1 will develop breast cancer, which has led some women who have the mutation to get preventative mastectomies. According to Inder Verma, a geneticist and molecular biologist at the Salk Institute for Biological Studies in San Diego, California, who headed the new study, BRCA’s role outside of the ovaries and breast are not as clear. It has been reported that mice bred without BRCA1 die soon after birth. This means that the gene is necessary to sustain life.
A student in Verma’s lab noticed that BRCA1 was very active in neuroectoderm. Neuroectoderm is a small sliver of embryonic tissue that contains neural stem cells that divide and differentiate into a number of different brain cells. Verma and coworkers were curious as to why BRCA1 was expressed at such high levels in this embryonic tissue and what would happen if they eliminated it. The researchers created a strain of mice which BRCA1 was knocked out only in neural stem cells. The researchers found that these mice developed a brain about one-third the size of normal mice. They also observed that there where reductions in brain areas that are involved with memory and learning, and that adult mice had a wobbly, drunken gait (ataxia). This neurological disorder affects muscle control and balance.
The next step was to determine why deleting BRCA1 had caused so many problems. They observed that neural stem cells were dividing at a normal rate, but many of these cells died soon after they formed. The researchers also observed that BRCA1 proteins were helping to keep DNA from crumbling as the cells divided. Without BRCA-induced repair of DNA, ATM kinase senses excess DNA fragments and activates a chemical pathway that kills off damaged cells. So, mice with defective BRCA1 genes had many more cells eliminated than what would occur in normal brain development. It was also observed that many of the cells that survived were malformed and disorganized. Verma notes,
The cellular disarray is similar to that seen in cancer. Both cancer cells and the brain cells show “no orderly conduct.” The research suggests that BRCA may play a role in the evolution of brain size. Genes known to be involved with generating microcephaly (small brain) directly control the levels of BRCA1 expression.
Jeremy Pulvers, a molecular biologist at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, notes, this new study “provides further evidence that BRCA1 … plays a specific role in brain size regulation”. Huda Zoghbi, professor of Molecular and Human Genetics at Baylor College of Medicine in Houston, Texas, notes, “This is important fundamental basic science about how the genome is protected in rapidly proliferating cells in the brain.” The McGovern Institute for Brain Research at MIT announced this week that Zoghbi was awarded the 2014 Edward M. Scolnick Prize in Neuroscience. The McGovern Institute annually awards $100,000 to outstanding advances in the field of neuroscience.
Zoghbi studies the genetic basis of human brain disorders such as Rett Syndrome. Rett Syndrome is a neurological disease that affects young girls (males with this disease generally die in infancy). Girls with Rett Syndrome develop normally for one or two years, but then begin to show progressive loss of motor skills, speech and other cognitive abilities and many of them develop autism. Zoghbi was able to demonstrate that Rett Syndrome is caused by a deficiency in the protein MeCP2 which binds to methylated DNA and regulates the expression of many other genes.