Neurofibromatosis-1 Gene Regulation of Stem Cell Function May Underlie the Pattern of Brain Tumor Formation in NF1

October 15, 2010

Categories: 2010 Articles

Researchers at the Washington University Neurofibromatosis (NF) Center have found that the neurofibromatosis-1 gene is an essential driver of early brain development. However, there was an unexpected twist to the story.A new study from David H. Gutmann, MD, PhD and his colleagues showed that the neurofibromatosis 1 (NF1) gene helps push stem cells in the brain (neural stem cells) to grow and develop into astrocytes. Interestingly, they now report in the journal Genes and Development that neural stem cells from different regions of the brain are not all equally affected by mutation of the NF1 gene.

Children with NF1, a common tumor predisposition syndrome, develop brain tumors, called gliomas (or astrocytomas), which are composed of cancerous stem cells. These gliomas arise following loss of NF1 gene function as a result of genetic mutation. While the NF1 gene is expressed in neural stem cells from all brain regions, gliomas most commonly form in the optic nerve and brainstem, and rarely in other brain areas.

“While there may be many reasons for this unique pattern of brain tumor development, it is possible that the cells that give rise to gliomas, like stem cells, may vary in their response to NF1 gene mutation”, says Gutmann, the Donald O. Schnuck Family Professor in Neurology and Director of the Washington University NF Center. “In this way, stem cells from one part of the brain may increase their growth and formation of astrocytes, while stem cells from another region might not.”

Researchers led by Da Yong Lee, Ph.D., a postdoctoral fellow in Dr. Gutmann’s laboratory, demonstrated that neural stem cells from the brainstem grow faster and form more astrocytes upon mutation of the mouse Nf1 gene. In striking contrast, neural stem cells from the cortex, a region where gliomas uncommonly form in children with NF1, do not grow faster or produce more astrocytes following Nf1 gene loss.

Dr. Lee and her colleagues further uncovered the reason for these brain region-specific differences, and found that neural stem cells from the brainstem express high levels of a protein that promotes stem cell growth and astrocyte differentiation, while those from the cortex do not.

“These findings suggest that the pattern of brain tumor formation in children with NF1 in part reflects the unique properties of stem cells from different regions of the brain,” Gutmann says, “and argues that future brain tumor treatments should be tailored to the specific abilities of cancer cells from different brain areas.”

Gutmann and associates are currently planning additional studies to understand how differences in neural stem cell function vary from region to region within the brain, and how these differences can be exploited to develop targeted therapies for brain tumors and other diseases affecting the nervous system.