Global expression of NGF promotes sympathetic axonal growth in CNS white matter but does not alter its parallel orientation

• Published in: Experimental neurology 2007-01, Vol.203 (1), p.95-109
• Main Authors: Pettigrew, David B., Li, Ya-Qin, Kuntz, Charles, Crutcher, Keith A.
• Format: Article
• Language: English
• Subjects: Animals; Astrocyte; Astrocytes - cytology; Astrocytes - physiology; Axonal guidance; Axonal regeneration; Axotomy; Biological and medical sciences; Brain Injuries - metabolism; Brain Injuries - physiopathology; Brain Injuries - therapy; Brain Injury, Chronic - metabolism; Brain Injury, Chronic - physiopathology; Brain Injury, Chronic - therapy; Central Nervous System - cytology; Central Nervous System - metabolism; Chemotropism; Chondroitin Sulfate Proteoglycans - metabolism; Cicatrix - physiopathology; Cicatrix - prevention & control; Geometry; GFAP; Glial Fibrillary Acidic Protein - genetics; Glial Fibrillary Acidic Protein - metabolism; Gradient; Graft Survival - physiology; Growth Cones - metabolism; Growth Cones - ultrastructure; Injuries of the nervous system and the skull. Diseases due to physical agents; Laminin; Medical sciences; Mice; Mice, Transgenic; Nerve Fibers, Myelinated - metabolism; Nerve Fibers, Myelinated - ultrastructure; Nerve Growth Factor - genetics; Nerve Growth Factor - metabolism; Nerve Regeneration - physiology; Neurology; Neurotrophin; Neurotropism; Promoter Regions, Genetic - genetics; Superior Cervical Ganglion - cytology; Superior Cervical Ganglion - metabolism; Superior Cervical Ganglion - transplantation; Sympathetic Fibers, Postganglionic - cytology; Sympathetic Fibers, Postganglionic - metabolism; Sympathetic Fibers, Postganglionic - transplantation; Tissue Transplantation; Transgenic; Traumas. Diseases due to physical agents; Up-Regulation - physiology; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2006.07.026

Axonal regeneration is normally limited after injuries to CNS white matter. Infusion of neurotrophins has been successful in promoting regenerative growth through injured white matter but this growth generally fails to extend beyond the infusion site. These observations are consistent with a chemotropic effect of these factors on axonal growth and support the prevailing view that neurotrophin-induced axonal regeneration requires the use of gradients, i.e., gradually increasing neurotrophin levels along the target fiber tract. To examine the potential of global overexpression of neurotrophins to promote, and/or modify the orientation of, regenerative axonal growth within white matter, we grafted nerve growth factor (NGF) responsive neurons into the corpus callosum of transgenic mice overexpressing NGF throughout the CNS under control of the promoter for glial fibrillary acidic protein. One week later, glial fibrillary acidic protein and chondroitin sulfate proteoglycan immunoreactivity increased within injured white matter around the grafts. NGF levels were significantly higher in the brains of transgenic compared with non-transgenic mice and further elevated within injury sites compared with the homotypic region of the non-injured side. Although there was minimal outgrowth from neurons grafted into non-transgenic mice, extensive parallel axonal regeneration had occurred within the corpus callosum up to 1.5 mm beyond the astrogliotic scar (the site of maximum NGF expression) in transgenic mice. These results demonstrate that global overexpression of neurotrophins does not override the constraints limiting regenerative growth to parallel orientations and suggest that such factors need not be presented as positive gradients to promote axonal regeneration within white matter.