Regulation of axonal caliber, neurofilament content, and nuclear localization in mature sensory neurons by nerve growth factor.

The neuronal perikaryal response to axonal injury (axon reaction) includes reduction in axonal caliber beginning in the proximal portion of the nerve (somatofugal axonal atrophy), development of nuclear eccentricity, and chromatolysis. The means by which these events are triggered is unknown, but it has been argued that loss of a neurotrophic signal from the target of injured neurons plays a role. To date, the identity of this substance(s) remains unknown. In the present study, we have asked whether NGF normally functions to control axonal caliber of sensory neurons in the L4 and L5 dorsal root ganglia (DRG) of the adult rat. Two approaches were used: (1) NGF was continuously delivered to the proximal stump of a transected sciatic nerve to determine whether NGF administration would prevent the production of somatofugal axonal atrophy; and (2) NGF antisera were administered to normal animals to determine whether NGF deprivation would produce somatofugal axonal atrophy. In the first experiment, 9-week-old rats underwent a unilateral sciatic nerve transection at midthigh, and the proximal stump was connected to an osmotic pump containing either NGF or cytochrome C (as control). At 11 weeks of age, dorsal root fibers in lumbar DRG from the control group appeared smaller in caliber and less circular in shape than fibers from age-matched normal animals. Although smaller than those in normal animals, fibers from the NGF-treated nerves were larger than in axotomized controls. Mean axonal area and shape factor (an index in circularity) were measured and found to be decreased significantly (22% and 15%, respectively) from the control group. Fibers from the NGF-treated nerves were significantly (p less than 0.05) larger in axonal caliber and more circular in shape; mean values were only reduced by 11% and 10%, respectively. Quantitation of neurofilament (NF) numbers revealed that the larger calibers in the NGF-treated nerves result from a greater NF content. NGF treatment did not prevent the atrophy of motor fibers in the proximal ventral root. In the second experiment, 2 antisera to mouse NGF were given daily into the footpad for 11 or 12 d; control animals were given normal goat serum. Quantitation of axonal calibers in the L5 DRG demonstrated that mean axonal area and shape factor were significantly (p less than 0.05) reduced by 14% and 17% respectively. The axoplasm of atrophic fibers demonstrated a paucity of NFs.(ABSTRACT TRUNCATED AT 400 WORDS)