Cancer gene drives pivotal decision in early brain development

Abstract

A gene linked to pediatric brain tumors is anessential driver of early brain development, Siteman Cancer Centerresearchers at Washington University School of Medicine in St. Louishave found.

The study, published in October 2007 in Cell Stem Cell, reveals thatthe neurofibromatosis 1 (NF1) gene helps push stem cells downseparate paths that lead them to become two major types of braincells: support cells known as astrocytes and brain neurons.

The NF1 gene is mutated in the inherited medical condition known asneurofibromatosis type 1. The new results show that scientists likelywill need separate treatments to deal with this condition's two majorsymptoms, brain cancers and learning disabilities.

"Our findings also have potential implications for the general studyof brain development," says senior author David Gutmann, MD, PhD, theDonald O. Schnuck Family Professor of Neurology and director ofthe Washington University Neurofibromatosis Center. "Neuroscientistshave identified a number of genes that regulate brain celldevelopment, but this gene is particularly interesting because it isaffecting cells at a very early stage."

More than 100,000 people in the United States have neurofibromatosistype 1, making it the most common tumor predisposition syndromeaffecting the nervous system. The brain tumors that appear in 15 to20 percent of neurofibromatosis type 1 patients come from brainsupport cells known as astrocytes; in contrast, scientists believethe learning disabilities present in 60 percent to 70 percent ofthese patients are mainly due to problems in brain neurons. Thesesymptoms can occur individually or in combination.

This puzzled scientists - how was an alteration in one gene affectingtwo very different cell types? Astrocytes belong to a category ofbrain cells known as glial cells that support, protect and nourishneurons and regulate the brain environment. Neurons are believed todo the "work" of thought and memory using electrochemical signalsthat 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 thebrains of developing embryos. Researchers led by Balazs Hegedus, PhD,a postdoctoral fellow, developed a line of mice in which they couldselectively disable the mouse equivalent of the human NF1 gene, Nf1,in neural stem cells. Studies of these mice revealed that the Nf1protein, neurofibromin, controls the activity of two signalingpathways, the cyclic adenosine monophosphate (cAMP) pathway and theRas pathway. This allows neurofibromin to regulate the development ofboth neurons and astrocytes.

"We found that neurofibromin regulation of the Ras pathway isessential for the development of astrocytes but not for neurons,"Gutmann explains. "The opposite was true of the cAMP pathway - theeffect of neurofibromin on cAMP signaling was critical for neuronsbut not for astrocytes."

Gutmann suggests the search for treatments for neurofibromatosis type1 should branch out along a similar dual track."For patients with brain tumors, we probably need to focus onidentifying new or existing treatments that normalize Ras pathwayactivity," Gutmann says. "To treat the learning disabilities, weprobably need to focus on the cAMP pathway."

More details of the molecular mechanisms that push neural stem cellsonto the paths to becoming an astrocyte or a neuron may potentiallybe useful for understanding other developmental disorders of thebrain, according to Gutmann.

He and his colleagues plan to use this unique mouse model that letsthem selectively disable Nf1 in brain progenitor cells to betterunderstand the causes of neurofibromatosis type 1-related learningdisabilities. Anatomically, the brains of neurofibromatosis type 1patients contain no obvious structural defects that readily explainwhy the majority of children with the condition have learningdisabilities. Insights from the study of this Nf1 mouse strain mayprovide a hint to where the problems lie.

"In our investigations of the relationship of neurofibromin withneuronal differentiation, we found loss of Nf1 expression delayed theneuron's ability to make proteins important for growing newbranches," Gutmann says. "While we haven't proven this yet, ourstudies suggest a developing neuron's ability to make connectionswith other neurons might be impaired when the Nf1 gene isdysfunctional. Problems making proper connections could hamperlearning and memory."

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

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

Contact:

Michael Purdy; 314-286-0122; [email protected]