Desert hedgehog is a mediator of demyelination in compression neuropathies.
The secreted protein desert hedgehog (dhh) controls the formation of the nerve perineurium during development and is a key component of Schwann cells that ensures peripheral nerve survival. We postulated that dhh may play a critical role in maintaining myelination and investigated its role in demyelination-induced compression neuropathies by using a post-natal model of a chronic nerve injury in wildtype and dhh(-/-) mice. We evaluated demyelination using electrophysiological, morphological, and molecular approaches. dhh transcripts and protein are down-regulated early after injury in wild-type mice, suggesting an intimate relationship between the hedgehog pathway and demyelination. In dhh(-/-) mice, nerve injury induced more prominent and severe demyelination relative to their wild-type counterparts, suggesting a protective role of dhh. Alterations in nerve fiber characteristics included significant decreases in nerve conduction velocity, increased myelin debris, and substantial decreases in internodal length. Furthermore, in vitro studies showed that dhh blockade via either adenovirus-mediated (shRNA) or pharmacological inhibition both resulted in severe demyelination, which could be rescued by exogenous Dhh. Exogenous Dhh was protective against this demyelination and maintained myelination at baseline levels in a custom in vitro bioreactor to applied biophysical forces to myelinated DRG/Schwann cell co-cultures. Together, these results demonstrate a pivotal role for dhh in maintaining myelination. Furthermore, dhh signaling reveals a potential target for therapeutic intervention to prevent and treat demyelination of peripheral nerves in compression neuropathies.
Department of Orthopaedic Surgery, University of California, Irvine, CA 92697, USA.
James
J
Jung
Department of Orthopaedic Surgery, University of California, Irvine, CA 92697, USA.
Derek
D
Frump
Department of Orthopaedic Surgery, University of California, Irvine, CA 92697, USA.
Jared
J
Su
Department of Orthopaedic Surgery, University of California, Irvine, CA 92697, USA.
Weiping
W
Wang
Department of Orthopaedic Surgery, University of California, Irvine, CA 92697, USA; Department of Neurology, University of California, Irvine, CA 92697, USA.
Tahseen
T
Mozaffar
Department of Orthopaedic Surgery, University of California, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California, Irvine, CA 92697, USA; Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697, USA. Electronic address: ranjang@uci.edu.
Ranjan
R
Gupta
D000818:Animals; D000831:Animals, Newborn; D001176:Arthrogryposis / Q000150:complications*; D001369:Axons / Q000473:pathology; D018929:Cell Culture Techniques; D003711:Demyelinating Diseases / Q000209:etiology* / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D007839:Functional Laterality / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000502:physiology*; D053823:Hedgehog Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015417:Hereditary Sensory and Motor Neuropathy / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009431:Neural Conduction / Q000235:genetics; D009474:Neurons / Q000502:physiology; D010525:Peripheral Nerves / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000502:physiology
D053823:Hedgehog Proteins
Chronic nerve compression (CNC) injury; Compression neuropathy; Demyelination; Desert hedgehog; Peripheral nerve; Schwann cell