Depleting endogenous neurotrophin-3 enhances myelin formation in the Trembler-J mouse, a model of a peripheral neuropathy.
The heterozygous Trembler-J (TrJ/+) mouse, containing a point mutation in the peripheral myelin protein 22 (Pmp22) gene, is characterized by severe hypomyelination and is a representative model of Charcot-Marie-Tooth 1A (CMT1A) disease/Dejerine-Sottas syndrome (DSS). Given that the neurotrophin-3 (NT3)-TrkC signaling pathway is inhibitory to myelination during development, we investigated the role of the NT3-TrkC pathway in myelination and manipulated this pathway to improve myelin formation in the CMT1A/DSS mouse model. Injection of NT3 to the TrJ/+ mice decreased the myelin protein P(0) level in the sciatic nerves. Suppressing the NT3-TrkC pathway with TrkC-Fc, an NT3 scavenger, enhanced myelination in vitro and in vivo in the TrJ/+ mouse. Furthermore, we found that full-length TrkC was expressed in adult TrJ/+ mouse sciatic nerves but was not detected in the wild-type adults, suggesting that the full-length TrkC is a potential target of treatment to enhance myelination in the TrJ/+ mouse.
Liu
Ning
N
Department of Neurobiology, Stanford University School of Medicine, Stanford, California, USA.
Varma
Sushama
S
Tsao
David
D
Shooter
Eric M
EM
Tolwani
Ravi J
RJ
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D046529:Microscopy, Electron, Transmission / Q000379:methods; D018993:Myelin P0 Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D020933:Neurotrophin 3 / Q000172:deficiency* / Q000627:therapeutic use; D009924:Organ Culture Techniques; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D020812:Receptor, trkC / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism
D018993:Myelin P0 Protein; D020933:Neurotrophin 3; D009418:S100 Proteins; D020812:Receptor, trkC