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New Mouse Model for Neurofibromatosis Yields Insights into Disease Process and Treatment

For release: Monday, April 21, 2008

In a move expected to enhance the development of therapies for neurofibromatosis type 1, scientists have created an improved mouse model for the disease.

Neurofibromatosis type 1 is a genetic disease that causes tumors to grow within nerves.  Some tumors – called dermal neurofibromas – appear on the skin or just under the skin.  Others – called plexiform neurofibromas – sprout within deeper nerves, and may press against the spinal cord, bones, muscles and organs.

Neurofibromas can be surgically removed.  However, total removal is often not possible because the tumors are heavily intertwined with nerve tissue.  In rare cases when they become malignant, they can be targeted with chemotherapy or radiation, but in many cases the tumors cannot be eliminated.  There is currently no treatment to prevent neurofibromas from growing.

The new mouse model will "give us the opportunity to test a variety of potential therapies," says Nancy Ratner, Ph.D., a cell and cancer biologist at Cincinnati Children's Hospital Medical Center.  Dr. Ratner and colleagues developed the new model with support from the National Institute of Neurological Disorders and Stroke (NINDS).  Their work was published in the February 2008 issue of Cancer Cell*.

Investigators identified disease-causing mutations in the NF1 gene in 1990, but they have struggled to create a mouse model that faithfully reproduces the human disease.  Knockout mice that completely lack the NF1 gene die as embryos, while partial knockouts fail to develop dermal neurofibromas.  Dr. Ratner and her team generated mice in which NF1 is turned off at a discrete time, in a specific cell type during development.  Those mice survive through embryonic life, and eventually develop both kinds of neurofibromas.

In the new mouse model, tumors also form earlier and grow larger than in other models, which should make it easier to test potential therapies, Dr. Ratner says.  One type of therapy under consideration is the use of antifibrotic drugs that block the activity of growth factors that feed tumors.  Other experimental drugs inhibit the ras pathway – a trigger for cell division that becomes overactive in cells lacking the NF1 protein.

Experiments to test antifibrotics and other treatments in the mice are underway.  Meanwhile, the mice are already helping researchers answer questions that have hindered therapeutic development for decades.

One longstanding question has been the identity of the tumor-causing cell.  Most research points to Schwann cells, which form a protective sheath around nerve fibers, called myelin.  But neurofibromas contain other types of cells derived from the neural crest. During embryonic development, neural crest cells emerge from the edges of the developing spinal cord and fan outward to become Schwann cells, sensory and autonomic neurons, skin pigment cells and other cell types.  Researchers have wondered whether these other neural crest-derived cells contribute to the disease, and whether there is a role for non-neural crest cells in the tumors.

Another related issue concerns the effects of NF1 gene dosage in different cell types.  Normally, every cell in the body would contain two functional copies of the NF1 gene (one copy inherited from each parent).  Some people with neurofibromatosis are "somatic mosaic," meaning that some of their cells have two normal copies of NF1, while other cells have two mutant copies and still others are half and half (NF1+/-).  These NF1+/- cells have abnormal, tumor-like properties, suggesting that they might participate in the disease.

Dr. Ratner's mice carry an NF1 gene that is turned off in Schwann cells – but not other cell types – at a time when Schwann cells and neurons are forming nerves.  The results establish that complete absence of NF1 in developing Schwann cells is sufficient to cause neurofibromas.

The researchers also found that NF1 deficiency is most likely to trigger cell division and neurofibroma growth at an early phase of the Schwann cell life span.  In that set of experiments, the researchers grew neural crest-derived cells in culture, and inactivated the NF1 gene at different times.  Turning off the gene when the cells were beginning to take on the characteristics of immature Schwann cells caused them to divide and form colonies.  Turning off the gene at earlier or later points in time had no effect.

"Homing in on the tumor-causing cell, which appears to be something between a Schwann cell precursor and an immature Schwann cell, will enable us to examine how loss of NF1 stimulates tumor growth," Dr. Ratner says.  That knowledge could reveal new targets for drug development, she says.

NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services.  The NIH — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research. It investigates the causes, treatments, and cures for both common and rare diseases.  For more information about NIH and its programs, visit

*Wu J et al.  "Plexiform and Dermal Neurofibromas and Pigmentation Are Caused by Nf1 Loss in Desert Hedgehog-Expressing Cells."  Cancer Cell, February 2008, Vol. 13, pp. 1-12.

-By Daniel Stimson, Ph.D.

Last Modified April 25, 2008