Cancer gene drives pivotal decision in early brain development

November 13, 2007

Nov. 13, 2007 -- 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."
-end-
Hegedus B, Dasgupta B, Shin JE, Emnett RJ, Hart-Mahon EK, Elghazi L, Bernal-Mizrachi E, Gutmann DH. Neurofibromatosis-1 regulates neuronal and glial cell differentiation from neuroglial progenitors in vivo by both cAMP- and Ras-dependent mechanisms. Cell Stem Cell, October 11, 2007.

Funding from the U.S. Department of Defense and National Cancer Institute Mouse Models of Human Cancers Consortium supported this research.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Washington University in St. Louis

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.