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Growth factor stimulates rapid extension
of key motor neurons in brain
MGH study first to identify factors
controlling growth of brain cells damaged in ALS
BOSTON - November 3, 2006 - 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.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of nearly $500 million and
major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, transplantation biology and photomedicine. MGH and Brigham
and Women's Hospital are founding members of Partners HealthCare
HealthCare System, a Boston-based integrated health care delivery
system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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