MGH study first to identify factors controlling growth of brain cells damaged in ALS

A growth factor known to be important for the survival of many types of cells stimulates rapid extension of corticospinal motor neurons – critical brain cells that connect the cerebral cortex with the spinal cord and that die in motor neuron diseases like amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). In the November 2006 issue of Nature Neuroscience, two investigators from Massachusetts General Hospital (MGH) and the Harvard Stem Cell Institute describe how insulin-like growth factor 1 (IGF-1) dramatically increases the in vitro growth of corticospinal motor neuron (CSMN) axons – projections that carry nerve impulses to the spinal motor neurons that connect to muscles – and that blocking IGF-1 activity reduces that growth in both cultured cells and in living mice.
"Our findings that IGF-1 specifically enhances both the speed and extent of axon outgrowth of corticospinal motor neurons are the first direct evidence of growth factor control over the differentiation of these neurons, " says Jeffrey Macklis MD, DHST, director of the MGH-Harvard Medical School (HMS) Center for Nervous System Repair, the report's senior author. "In addition to providing insight into the development and circuit formation of this critical population of neurons, these results might lead to the future ability to treat motor neuron disorders and spinal cord injuries."
Although their cell bodies are located in the brain, CSMN axons extend down to the neurons they control in the spinal cord – extending as far as three feet in adult humans. These neurons degenerate in ALS and related disorders, and their damage contributes to loss of motor function in spinal cord injuries. Since they are embedded among hundreds of other types of neurons in the cerebral cortex, it has been difficult to study CSMN, and little has been known about cellular and molecular factors that control their growth and development. In order to study growth factor controls over these cells, Macklis and Hande Ozdinler, PhD, a postdoctoral fellow in his laboratory, developed a new way of isolating pure populations of CSMN in culture and found that IGF-1 was a prime candidate for control over CSMN development.
Using these purified neurons, they then showed that two ways of applying IGF-1 – generally adding it to culture dishes or placing IGF-1-coated microbeads right next to CSMN cell bodies – both increased the growth of axons by 15- to 20-fold, reaching the very fast rates previously seen only during initial development. Blocking the interaction between IGF-1 and its receptor reduced axon growth to control levels, confirming that the IGF-1 pathway is critical to the enhancement effect.
Experiments with another type of neuron and with several different growth factors verified that axonal growth was stimulated only by IGF-1 and only in CSMN. The researchers also showed that IGF-1 enhancement of axonal growth operates separately from the growth factor's known support of neuronal survival. Tests in living developing mice showed that blocking the IGF-1 pathway in the spinal cord prevented the growth of CSMN axons, which confirmed the applicability of the in vitro experiments to living mammals.
"The role of IGF-1 as a potent and specific enhancer of CSMN axon growth is highly relevant to our understanding of this critical population of neurons. These findings are a first step that may someday lead to ways of treating the neuronal degeneration of diseases like ALS, regenerating cells for the treatment of spinal cord injury, and to the potential replacement of neurons using precursors or 'neural stem cells'," says Macklis, who is on the faculty at Harvard Medical School.
The study was supported by grants from the National Institutes of Health, the ALS Association, and the Harvard Center for Neurodegeneration and Repair.
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