Overexpression of neurotrophin-3 in skeletal muscle alters normal and injury-induced limb control.
Transgenic overexpression of neurotrophin-3 (NT-3) in mice increases the number of surviving proprioceptive sensory components, including primary sensory neurons, gamma motoneurons and muscle spindles. The numbers of surviving alpha motoneurons are not affected by NT-3 overexpression (Wright et al., Neuron 19: 503-517, 1997). We have assessed the consequences NT-3-stimulated increase in the proprioceptive sensory system by measuring locomotive abilities of mice that overexpress NT-3 in all skeletal muscles (myo/NT-3 mice). In adulthood, one myo/NT-3 transgenic line continues to express NT-3 at high levels in muscle and maintains a hypertrophied proprioceptive system (high-OE myo/NT-3 mice). Compared to wildtypes, high-OE myo/NT-3 mice have nine times the amount of NT-3 protein in the medial gastrocnemius at six weeks of age. Although appearing normal during ordinary activity, high-OE myo/NT-3 mice display a distinct clasping phenotype when lifted by the tail. High-OE myo/NT-3 mice show severe locomotor deficits when performing beam walking and rotorod testing. These mice also demonstrate aberrant foot positioning during normal walking. However, following sciatic nerve crush, overexpression of NT-3 prevents further abnormalities in paw positioning, suggesting NT-3 may attenuate sensorimotor deficits that occur in response to sciatic nerve injury. Our results suggest that increases in proprioceptive sensory neurons, spindles and gamma motoneurons, along with continued postnatal NT-3 overexpression in muscle significantly disrupt normal locomotor control. Importantly, however, NT-3 may lessen initial deficits and thus improve functional recovery after peripheral nerve injury, suggesting these mice may serve as a good model to study NT-3's role in neuroprotection of proprioceptive afferents.
Taylor
M D
MD
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City 66160, USA.
Vancura
R
R
Williams
J M
JM
Riekhof
J T
JT
Taylor
B K
BK
Wright
D E
DE
D000818:Animals; D005121:Extremities / Q000294:innervation* / Q000502:physiology*; D005684:Gait; D005786:Gene Expression Regulation / Q000502:physiology*; D006614:Hindlimb / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D018008:Myogenin / Q000235:genetics; D009409:Nerve Crush; D009475:Neurons, Afferent / Q000502:physiology; D018696:Neuroprotective Agents; D020933:Neurotrophin 3 / Q000096:biosynthesis* / Q000235:genetics; D004856:Postural Balance / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011434:Proprioception / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology; D012584:Sciatic Nerve / Q000293:injuries*
C503801:Myog protein, mouse; D018008:Myogenin; D018696:Neuroprotective Agents; D020933:Neurotrophin 3