Muscle ciliary neurotrophic factor receptor α promotes axonal regeneration and functional recovery following peripheral nerve lesion

• Published in: Journal of comparative neurology (1911) 2013-09, Vol.521 (13), p.2947-2965
• Main Authors: Lee, Nancy, Spearry, Rachel P., Leahy, Kendra M., Robitz, Rachel, Trinh, Dennis S., Mason, Carter O., Zurbrugg, Rebekah J., Batt, Myra K., Paul, Richard J., Maclennan, A. John
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Axons - drug effects; Bacterial Proteins - metabolism; Body Weight - drug effects; Body Weight - genetics; Cell Survival - drug effects; Cell Survival - genetics; Ciliary Neurotrophic Factor Receptor alpha Subunit - genetics; Ciliary Neurotrophic Factor Receptor alpha Subunit - therapeutic use; Cre recombinase; Disease Models, Animal; Functional Laterality; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Luminescent Proteins - metabolism; Mice; Mice, Transgenic; mlc1f-Cre; Motor Neurons - drug effects; Motor Neurons - physiology; mouse; muscle CNTF receptor α; Muscle Contraction - drug effects; Muscle Contraction - genetics; Muscle Fibers, Skeletal - pathology; Nerve Regeneration - drug effects; Nerve Regeneration - genetics; Neuromuscular Junction - drug effects; Neuromuscular Junction - pathology; Receptors, Cholinergic - metabolism; Recovery of Function - drug effects; Recovery of Function - genetics; RNA, Messenger; sciatic; Sciatic Neuropathy - drug therapy; Sciatic Neuropathy - pathology; Sciatic Neuropathy - physiopathology; Stilbamidines; Walking - physiology
• ISSN: 0021-9967; 1096-9861
• DOI: 10.1002/cne.23324

ABSTRACT Ciliary neurotrophic factor (CNTF) administration maintains, protects, and promotes the regeneration of both motor neurons (MNs) and skeletal muscle in a wide variety of models. Expression of CNTF receptor α (CNTFRα), an essential CNTF receptor component, is greatly increased in skeletal muscle following neuromuscular insult. Together the data suggest that muscle CNTFRα may contribute to neuromuscular maintenance, protection, and/or regeneration in vivo. To directly address the role of muscle CNTFRα, we selectively‐depleted it in vivo by using a “floxed” CNTFRα mouse line and a gene construct (mlc1f‐Cre) that drives the expression of Cre specifically in skeletal muscle. The resulting mice were challenged with sciatic nerve crush. Counting of nerve axons and retrograde tracing of MNs indicated that muscle CNTFRα contributes to MN axonal regeneration across the lesion site. Walking track analysis indicated that muscle CNTFRα is also required for normal recovery of motor function. However, the same muscle CNTFRα depletion unexpectedly had no detected effect on the maintenance or regeneration of the muscle itself, even though exogenous CNTF has been shown to affect these functions. Similarly, MN survival and lesion‐induced terminal sprouting were unaffected. Therefore, muscle CNTFRα is an interesting new example of a muscle growth factor receptor that, in vivo under physiological conditions, contributes much more to neuronal regeneration than to the maintenance or regeneration of the muscle itself. This novel form of muscle–neuron interaction also has implications in the therapeutic targeting of the neuromuscular system in MN disorders and following nerve injury. J. Comp. Neurol. 521: 2947–2965, 2013. © 2013 Wiley Periodicals, Inc. We selectively depleted muscle ciliary neurotrophic factor receptor α (CNTFRα), an essential CNTF receptor component, in vivo and found that it contributes to motor neuron axonal regeneration across the site of peripheral nerve lesions and normal recovery of motor function. Surprisingly, we found no role for muscle CNTFRα in the maintenance or regeneration of the muscle itself.