Neuritin mediates nerve growth factor-induced axonal regeneration and is deficient in experimental diabetic neuropathy.
OBJECTIVE
Axonal regeneration is defective in both experimental and clinical diabetic neuropathy, contributing to loss of axonal extremities and neuronal dysfunction. The mechanisms behind this failure are not fully understood; however, a deficit in neurotrophic support and signaling has been implicated.


METHODS
We investigated the expression of neuritin (also known as candidate plasticity gene 15, cpg15) in the sensory nervous system of control rats and rats with streptozotocin (STZ)-induced diabetes using microarray PCR, Western blotting, and immunocytochemical analysis. The functional role of neuritin in sensory neurons in vitro was assessed using silencing RNA.


RESULTS
Neuritin was expressed by a population of small-diameter neurons in the dorsal root ganglia (DRG) and was anterogradely and retrogradely transported along the sciatic nerve in vivo. Nerve growth factor (NGF) treatment induced an increase in the transcription and translation of neuritin in sensory neurons in vitro. This increase was both time and dose dependent and occurred via mitogen-activated protein kinase or phosphatidylinositol-3 kinase activation. Inhibition of neuritin using silencing RNA abolished NGF-mediated neurite outgrowth, demonstrating the crucial role played by neuritin in mediating regeneration. Neuritin levels were reduced in both the DRG and sciatic nerve of rats with 12 weeks of STZ-induced diabetes, and these deficits were reversed in vivo by treatment with NGF.


CONCLUSIONS
Manipulation of neuritin levels in diabetes may therefore provide a potential target for therapeutic intervention in the management of neuropathy.
Karamoysoyli
Eugenia
E
Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
Burnand
Rebecca C
RC
Tomlinson
David R
DR
Gardiner
Natalie J
NJ
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000473:pathology / Q000503:physiopathology*; D058851:GPI-Linked Proteins; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017208:Rats, Wistar
D058851:GPI-Linked Proteins; D009479:Neuropeptides; C105161:Nrn1 protein, rat; D020932:Nerve Growth Factor