In amyotrophic lateral sclerosis (ALS, also called Lou Gehrig's disease), corticospinal neurons progressively degenerate, causing the loss of motor function and eventual paralysis seen in these individuals. Damage to these neurons also contributes to the loss of motor function in spinal cord injury. However, little is known about the mechanisms that regulate the survival and differentiation of corticospinal neurons. A paper on page 1371 by Hande Özdinler and Jeffrey Macklis describes new techniques to purify and culture these motor neurons, allowing the authors to dissect the mechanisms by which the morphology of these neurons is regulated.
The authors retrogradely labeled corticospinal neurons with fluorescent microspheres and used fluorescence-activated cell sorting to obtain homogeneous populations. These cultured neurons maintained the morphological and molecular phenotypes of developing corticospinal neurons in vivo. Insulin-like growth factor (IGF-1) specifically enhanced axonal outgrowth in these neurons, an effect mediated by the IGF-1 receptor and the PI3K and MAPK signaling pathways. Brain-derived neurotrophic factor, in contrast, induced dendritic branching and outgrowth, but did not affect axonal outgrowth. In vivo blockade of the IGF-1 receptor caused axonal outgrowth defects in the corticospinal tract. Critically, this effect of IGF-1 was independent of its effect on survival of these neurons, as corticospinal neurons isolated from mice lacking the apoptosis protein Bax behaved similarly to wild-type neurons in response to locally applied IGF-1. By demonstrating that IGF-1 is a potent enhancer of axonal outgrowth in corticospinal neurons, these results may help guide future efforts to use IGF-1 to enhance the outgrowth and functional connectivity of damaged neurons in diseases such as ALS and primary lateral sclerosis.
