Salk Associate Professor Sam Pfaff and postdoctoral fellow Soo-Kyung Lee reported in a paper in the June 5 issue of Neuron that they constructed a detailed model of how stem cells are prodded, regulated and otherwise encouraged to become not only nerve cells, but specifically motor neurons that the body relies on to move muscles and limbs throughout the body.
The study provides the first blueprint for the cellular factory that produces motor neurons from embryonic stem cells. It could eventually result in new treatments for spinal cord injury, and other diseases that affect motor nerve cells.
"In the embryonic nervous system, many types of neurons are generated with distinct properties, " said Pfaff. "We used nature as a model to understand how genes interact to develop motor nerves in the spinal cord. This study showed an unusually efficient yield of 60 percent motor nerves."
Working with chick embryo cells, the researchers achieved this efficiency by tracing how two important gene and protein-regulated pathways of nerve generation collaborate to create specialized nerve cells, including motor neurons. One pathway, called bHLH (short for basic-helix-loop-helix), creates a wide range of neurons from simple stem cells. The other pathway, called LIM Homeodomain (or LIM-D), determines what type of neuron is produced.
This study demonstrates how these two pathways interact, comprising the cellular factory that makes motor neuron. Using biochemical techniques and testing mutations in key pathway genes, Pfaff and his team worked out a model for how these nerve cells were formed. Knowing how this model works is crucial for producing new neurons, especially in adults.
"In adults, the growth cues that produce motor neurons from stem cells are gone," said Pfaff. "The signaling is gone after development is over, denying new, transplanted cells any cues for growth. This model, if it proves effective in humans, may help re-create those cues to help treat these injuries and diseases."
The principles that emerge from this study provide a framework for generating other classes of neurons such as those affected in Parkinson's disease. Because there currently is no effective treatment for these disorders, this study and similar scientific investments in understanding the basic mechanisms of growth and injury may pay off in future treatments.
Pfaff's work is supported by the National Institute of Neurological Diseases and Stroke, the Pew Charitable Trusts and the G. Harold and Leila Y. Mathers and Chun foundations.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. Jonas Salk, M.D., founded the institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.