Researchers at Dana-Farber Cancer Institute have compiled the first atlas showing the locations of crucial gene regulators, or switches that determine how different parts of the brain develop – and, in some cases, develop abnormally or malfunction.
The scientists say the map will accelerate research on brain tumors and neurological diseases that result from mutations in these switch genes – called “transcription factors.” When these genes are altered, the genes they control can go awry, causing abnormalities in the development or function of nerves and related structures.
Although the gene regulators were pinpointed using mouse brains, the map applies to the human brain as well.
“This is the first systematic mapping of all of the major brain areas that shows what regulatory genes are expressed in those specific locations,” said Quifu Ma, PhD, of Dana-Farber’s Cancer Biology Department. He is senior author of a paper appearing in today’s online issue of the journal Science, along with Charles D. Stiles, PhD, also of Dana-Farber.
Transcription factors are genes that control the expression, or activity, of “target” genes. These factors play a pivotal role in brain development by direction the formation of neurons and supporting cells called glia from uncommitted progenitor cells. Until now, brain transcription factors had not been systematically isolated and their locations within different parts of the brain pinned down.
The map should tell scientists studying different parts of the brain, which transcription factor (TF) genes regulate the development of that brain region, and which of them to investigate as possible causes of brain tumors and other diseases.
The Dana-Farber researchers already have homed in on specific TF genes regulating nerves involved in pain sensation, certain brain tumors, and speech problems caused by abnormally developing motor neurons that control muscles of the tongue.
The map, known as the Mahoney Transcription Factor Atlas, has been placed online where it is freely accessible to researchers studying brain development and disorders.
To compile the atlas, the investigators first sifted through databases of information from the Human Genome Project, singling out all genes in the mouse that appeared to be transcription factors: they turned up 1,445 of them. Next, they determined that more than 1,000 of these TF’s were expressed in the brains of developing mice.
Using genetic probes to investigate thin sections of mouse brains, the scientists found that only 349 of the TF genes were expressed in specific regions, and not throughout the brain, as the majority were. They inferred that these 349 genes, therefore, controlled the development of the particular areas or structures in which they were uniquely expressed.
“This is a manageable subset of transcription factors that are spatially restricted,” said Stiles. “This tells you that a particular transcription factor is involved in the formation of some specific kind of cell.”
Stiles is pursuing TF’s that direct the formation of astrocytes, which are affected in tumors called gliomas. David Rowitch, MD, PhD, of Dana-Farber and an author on the paper, studies transcription factors in the brain’s cerebellum, where tumors called medulloblastomas occur, and Ma has identified TF’s that regulate the nerves involved in the sensation of specific types of pain. Ma’s laboratory is focused on the stubborn problem of cancer pain: He and his students are screening the atlas for transcription factors that regulate development of the neurons that generate the severe pain that is a common symptom of metastatic tumors.
The research was funded by the Charles Dana Foundation, the National Institutes of Health, and individual fellowships.
Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.