Adult ciliary neurotrophic factor receptors help maintain facial motor neuron choline acetyltransferase expression in vivo following nerve crush.

Exogenous ciliary neurotrophic factor (CNTF) administration promotes the survival of motor neurons in a wide range of models. It also increases the expression of the critical neurotransmitter enzyme choline acetyltransferase (ChAT) by in vitro motor neurons, likely independent of its effects on their survival. We have used the adult mouse facial nerve crush model and adult-onset conditional disruption of the CNTF receptor α (CNTFRα) gene to directly examine the in vivo roles played by endogenous CNTF receptors in adult motor neuron survival and ChAT maintenance, independent of developmental functions. We have previously shown that adult activation of the CreER gene construct in floxed CNTFRα mice depletes this essential receptor subunit in a large subset of motor neurons (and all skeletal muscle, as shown in this study) but has no effect on the survival of intact or lesioned motor neurons, indicating that these adult CNTF receptors play no essential survival role in this model, in contrast to their essential role during embryonic development. Here we show that this same CNTFRα depletion does not affect ChAT labeling in nonlesioned motor neurons, but it significantly increases the loss of ChAT following nerve crush. The data suggest that, although neither motor neuron nor muscle CNTF receptors play a significant, nonredundant role in the maintenance of ChAT in intact adult motor neurons, the receptors become essential for ChAT maintenance when the motor neurons are challenged by nerve crush. Therefore, the data suggest that the receptors act as a critical component of an endogenous neuroprotective mechanism. J. Comp. Neurol. 525:1206-1215, 2017. © 2016 Wiley Periodicals, Inc.

Muscle and motor neuron ciliary neurotrophic factor receptor α together maintain adult motor neuron axons in vivo.

The molecular mechanisms maintaining adult motor innervation are comparatively unexplored relative to those involved during development. In addition to the fundamental neuroscience question, this area has important clinical ramifications given that loss of neuromuscular contact is thought to underlie several adult onset human neuromuscular diseases including amyotrophic lateral sclerosis. Indirect evidence suggests that ciliary neurotrophic factor (CNTF) receptors may contribute to adult motor neuron axon maintenance. To directly address this in vivo, we used adult onset mouse genetic disruption techniques to deplete motor neuron and muscle CNTF receptor α (CNTFRα), the essential ligand binding subunit of the receptor, and incorporated reporters labelling affected motor neuron axons and terminals. The combined depletion of motor neuron and muscle CNTFRα produced a large loss of motor neuron terminals and retrograde labelling of motor neurons with FluoroGold indicated axon die-back well beyond muscle, together revealing an essential role for CNTFRα in adult motor axon maintenance. In contrast, selective depletion of motor neuron CNTFRα did not affect motor innervation. These data, along with our previous work indicating no effect of muscle specific CNTFRα depletion on motor innervation, suggest that motor neuron and muscle CNTFRα function in concert to maintain motor neuron axons. The data also raise the possibility of motor neuron and/or muscle CNTFRα as therapeutic targets for adult neuromuscular denervating diseases.