Neurotrophin‐3 ameliorates sensory–motor deficits in Er81‐deficient mice

Abstract

Two factors, the ETS transcription factor ER81 and skeletal muscle-derived neurotrophin-3 (NT3), are essential for the formation of muscle spindles and the function of spindle afferent-motoneuron synapses in the spinal cord. Spindles either degenerate completely or are abnormal, and spindle afferents fail to project to spinal motoneurons in Er81 null mice; however, the interactions between ER81 and NT3 during the processes of afferent neuron and muscle spindle development are poorly understood. To examine if overexpression of NT3 in muscle rescues spindles and afferent-motoneuron connectivity in the absence of ER81, we generated myoNT3;Er81 ؊/؊ double-mutant mice that selectively overexpress NT3 in muscle in the absence of ER81. Spindle reflex arcs in myoNT3;Er81 ؊/؊ mutants differed greatly from Er81 null mice. Muscle spindle densities were greater and more afferents projected into the ventral spinal cord in myoNT3;Er81 ؊/؊ mice. Spindles of myoNT3;Er81 ؊/؊ muscles responded normally to repetitive muscle taps, and the monosynaptic inputs from Ia afferents to motoneurons, grossly reduced in Er81 ؊/؊ mutants, were restored to wild-type levels in myoNT3;Er81 ؊/؊ mice. Thus, an excess of muscle-derived NT3 reverses deficits in spindle numbers and afferent function induced by the absence of ER81. We conclude that muscle-derived NT3 can modulate spindle density and afferent-motoneuron connectivity independently of ER81.

Prenatal Exposure to Elevated NT3 Disrupts Synaptic Selectivity in the Spinal Cord

“…A possible explanation was that an increase in the number of Ia sensory neurons was directly responsible for the larger Ia inputs to MNs. Embryonic overexpression of NT3 is known to result in increased numbers of muscle spindles and Ia afferents (Oakley et al, 1995;Wright et al, 1997;Li et al, 2006), including a moderate increase in the number of large-diameter sensory afferents in mlc/NT3 mice (Taylor et al, 2001). We found no significant increase in the density of Ia collateral axons in the ventral horns of mlc/NT3 mice, however.…”

“…In examining the influence of NT3 on the formation of sensory motor synapses in mice lacking the transcription factor Er81 (Li et al, 2006), we discovered an additional unexpected role of this neurotrophin in the development of the stretch reflex circuit. Prenatal exposure to elevated levels of NT3 results in a major disruption of the pattern of monosynaptic connections between Ia afferents and MNs.…”

Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia

“…In DRG explants cultured from E11.5 and E12.5 embryos, NT3 but not NGF rapidly (within 3 h) induces the expression of Er81 immunoreactivity suggesting the direct regulation of this transcription factor by NT3 . Since ventral spinal cord projection and monosynaptic inputs from Ia afferents to motoneurons are restored in Er81 mutant mice transgenically expressing NT3 under the control of the myogenin promoter (Li et al 2006), NT3 appears to act independently of Er81 on central proprioceptor targeting.…”

Onset of ETS expression is not accelerated by premature exposure to signals from limb mesenchyme

“…In the absence of ER81, most Ia afferents fail to project into the ventral horn and do not form monosynaptic connections with homonymous motor neurons (Arber et al, 2000;Kucera et al, 2002). Of interest, the few remaining Ia-motor neuron connections are correct, indicating that ER81 is not responsible for the exquisite specificity of these monosynaptic connections (Li et al, 2006). PEA3 function in motor neurons is better understood.…”

“…Other earlier factors must establish the competence to express PEA3, because only the appropriate motor neurons express PEA3 upon exposure to GDNF in vitro (Haase et al, 2002). Neurotrophin-3 (NT3) triggers expression of ER81 in sensory neurons, but not in motor neurons (Patel et al, 2003;Li et al, 2006). We have previously shown that peripheral signals sculpt Er81 expression in motor neurons from a broader competence domain (Wang and Scott, 2004).…”