Motor Neuron Diversity in Development and Disease

Abstract

Although often considered as a group, spinal motor neurons are highly diverse in terms of their morphology, connectivity, and functional properties and differ significantly in their response to disease. Recent studies of motor neuron diversity have clarified developmental mechanisms and provided novel insights into neurodegeneration in amyotrophic lateral sclerosis (ALS). Motor neurons of different classes and subtypes--fast/slow, alpha/gamma--are grouped together into motor pools, each of which innervates a single skeletal muscle. Distinct mechanisms regulate their development. For example, glial cell line-derived neurotrophic factor (GDNF) has effects that are pool-specific on motor neuron connectivity, column-specific on axonal growth, and subtype-specific on survival. In multiple degenerative contexts including ALS, spinal muscular atrophy (SMA), and aging, fast-fatigable (FF) motor units degenerate early, whereas motor neurons innervating slow muscles and those involved in eye movement and pelvic sphincter control are strikingly preserved. Extrinsic and intrinsic mechanisms that confer resistance represent promising therapeutic targets in these currently incurable diseases.

IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1

“…The implication of a Bax-dependent pathway is consistent with some evidence demonstrating that the classical mitochondrial pathway has a function in the pathogenic process of motoneuron disease. 1,18 However, several arguments indicate that alternative cell death mechanisms may participate in the neurodegenerative process: overexpression of Bcl-2 in mutant SOD1 mice delays the onset but has no effect on the duration of the disease; 34 the targeted deletion of caspase-11 in SOD1 G93A mice, which results in a marked reduction of caspase-3 activity, failed to prevent neurodegeneration; 35 Bax deletion in mutant SOD1 mice does not prevent neuromuscular denervation and the fatal outcome of the disease. 36 Here, we show that ablating LIGHT, which triggers death of motoneurons following a differential mitochondrial execution phase, delays progression of the disease and increases motoneuron survival in SOD1 G93A mice.…”

“…Mice expressing human SOD1 mutations develop a motor syndrome with features of the human disease. 1 Both cell-autonomous and non-cell-autonomous processes contribute to motoneuron degeneration: a toxic action of mutant SOD1 within motoneurons has been documented as crucial for the onset and the early phase of disease progression, 2 whereas a non-cell-autonomous component, involving damage to astrocytes and microglia is determinant for disease progression. 3 Astrocytes have a pivotal role in the pathogenic process by determining the extent of the inflammatory response from microglia, 3 but also by releasing soluble factors selectively toxic for motoneurons.…”

Pool-Specific Regulation of Motor Neuron Survival by Neurotrophic Support

“…1) (Kablar and Rudnicki, 1999). While some mechanistic origins of differences in initial MN numbers are known (Dasen and Jessell, 2009;Kanning et al, 2010), evidence for pool-specific regulation of MN survival is still lacking, despite the plethora of factors exerting trophic support on cultured MN subsets (Henderson, 1996;Oppenheim, 1996).…”

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation

“…Additional pathological features include neuromuscular junction (NMJ) denervation, axonal degeneration, and abortive collateral sprouting (10,11). The combination of progressive motor neuron cell death and the retraction of axons from NMJs together with an impaired ability of surviving intact axons to generate compensatory axonal collateral sprouts results in progressive irreversible muscle atrophy (2,12,13).…”