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Spotlight

In a paper published in Nature Neuroscience, two investigators from the Harvard Stem Cell Institute and Massachusetts General Hospital 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, leader of HSCI's Nervous System Diseases Program. "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. Because CSMN are embedded among hundreds of other types of neurons in the cerebral cortex, it has been difficult to study these cells, and little is 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.

The team showed that if IGF-1 was applied to a pure population of CSMN, either by generally adding it to culture dishes or placing IGF-1-coated microbeads right next to CSMN cell bodies, the growth of axons increased by 15- to 20-fold, reaching 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.

Fig. 1. IGF-I induces a marked and specific increase in CSMN axon outgrowth. Camera lucida drawings of representative CSMN in control (a), IGF-I (b) or BDNF (c) conditions; quantitative analysis included assessment of axon length (dotted lines) and process complexity via Sholl analysis (concentric circles). (d) Bar graph of soma diameter of CSMN cultured in the presence of control medium, IGF-I or BDNF. (e) Bar graph representation of average CSMN axon length when cultured in the presence of control medium, IGF-I or BDNF. IGF-I induced substantially longer axons, whereas BDNF resulted in modestly reduced axon length compared to control. (f) Frequency histogram of the percentage of CSMN with axons of different length. In IGF-I, there was a marked shift to much longer axons, with many fewer short axons, compared to either control medium or BDNF. (g) Bar graph representation of the average number of branch points per CSMN in the presence of control medium, IGF-I or BDNF. BDNF markedly increased CSMN process branching. (h) Sholl analysis of CSMN cultured in the presence of control medium, IGF-I or BDNF. Error bars indicate s.e.m.

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 factors 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," says Macklis. "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'."

Ozdinler PH, Macklis JD. IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat Neurosci. 2006 Nov;9(11):1371-1381. Read Abstract.

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