Neurofibromatosis 1 gene drives pivotal decision in early brain development

A gene linked to pediatric brain tumors is an essential driver of early brain development, researchers at Washington University School of Medicine in St. Louis have found.

The study, published in October in Cell Stem Cell, reveals that the neurofibromatosis 1 (NF1) gene helps push stem cells down separate paths that lead them to become two major types of brain cells: support cells known as astrocytes and brain neurons.

The NF1 gene is mutated in the inherited medical condition known as neurofibromatosis type 1. The new results show that scientists likely will need separate treatments to deal with this condition's two major symptoms, brain cancers and learning disabilities.

"Our findings also have potential implications for the general study of brain development," says senior author David H. Gutmann, M.D., Ph.D., the Donald O. Schnuck Family Professor of Neurology and director of the Washington University Neurofibromatosis Center. "Neuroscientists have identified a number of genes that regulate brain cell development, but this gene is particularly interesting because it is affecting cells at a very early stage."

More than 100,000 people in the United States have neurofibromatosis type 1, making it the most common tumor predisposition syndrome affecting the nervous system. The brain tumors that appear in 15 to 20 percent of neurofibromatosis type 1 patients come from brain support cells known as astrocytes; in contrast, scientists believe the learning disabilities present in 60 to 70 percent of these patients are mainly due to problems in brain neurons. These symptoms can occur individually or in combination.

This puzzled scientists — how was an alteration in one gene affecting two very different cell types? Astrocytes belong to a category of brain cells known as glial cells that support, protect and nourish neurons and regulate the brain environment. Neurons are believed to do the "work" of thought and memory using electrochemical signals that they exchange with each other.

For answers, Gutmann and his colleagues turned to neural stem cells, the progenitor cells that give rise to neurons and astrocytes in the brains of developing embryos. Researchers led by Balazs Hegedus, Ph.D., a postdoctoral fellow, developed a line of mice in which they could selectively disable the mouse equivalent of the human NF1 gene, Nf1, in neural stem cells. Studies of these mice revealed that the Nf1 protein, neurofibromin, controls the activity of two signaling pathways, the cyclic adenosine monophosphate (cAMP) pathway and the Ras pathway. This allows neurofibromin to regulate the development of both neurons and astrocytes.

"We found that neurofibromin regulation of the Ras pathway is essential for the development of astrocytes, but not for neurons," Gutmann explains. "The opposite was true of the cAMP pathway — the effect of neurofibromin on cAMP signaling was critical for neurons but not for astrocytes."

Gutmann suggests the search for treatments for neurofibromatosis type 1 should branch out along a similar dual track.

"For patients with brain tumors, we probably need to focus on identifying new or existing treatments that normalize Ras pathway activity," Gutmann says. "To treat the learning disabilities, we probably need to focus on the cAMP pathway."

More details of the molecular mechanisms that push neural stem cells onto the paths to becoming an astrocyte or a neuron may potentially be useful for understanding other developmental disorders of the brain, according to Gutmann.

He and his colleagues plan to use this unique mouse model that lets them selectively disable Nf1 in brain progenitor cells to better understand the causes of neurofibromatosis type 1-related learning disabilities. Anatomically, the brains of neurofibromatosis type 1 patients contain no obvious structural defects that readily explain why the majority of children with the condition have learning disabilities. Insights from the study of this Nf1 mouse strain may provide a hint to where the problems lie.

"In our investigations of the relationship of neurofibromin with neuronal differentiation, we found loss of Nf1 expression delayed the neuron's ability to make proteins important for growing new branches," Gutmann says. "While we haven't proven this yet, our studies suggest a developing neuron's ability to make connections with other neurons might be impaired when the Nf1 gene is dysfunctional. Problems making proper connections could hamper learning and memory."

Gutmann plans additional studies of the mouse model to investigate the possibility that stem cells are critical contributors to the formation and maintenance of neurofibromatosis type 1 brain tumors.

"Because they lack the constraints on growth and replication present in more mature cells, stem cells are being studied more intensively as an important cell type to target in cancer therapy," Gutmann says. "The mice developed in this study will be invaluable to help address the role of stem cells in brain tumor formation and growth."