NGF AND NT-3 HAVE DIFFERING EFFECTS ON THE GROWTH OF DORSAL-ROOT AXONS IN DEVELOPING MAMMALIAN SPINAL-CORD

The functions of neurotrophins in relation to axon growth and branchin g during development of the nervous system are unknown. In order to ad dress this question, we have investigated the influences of systemical ly administered mouse nerve growth factor (mNGF) and human recombinant neurotrophin-3 (hrNT-3) on dorsal root axon growth in the spinal cord of embryonic rats. As anticipated, mNGF has a marked influence on gro wth of dorsal root axons. In mNGF-treated animals, dorsal root axons i n the developing dorsal funiculi and axon collaterals in developing gr ay matter are substantially longer than those of age-matched controls. Furthermore, growth cones of some dorsal root axons have more than tw ice the surface area of controls. These effects of NGF are highly sele ctive. Dorsal root axons that occupy a lateral position in white matte r and that normally give off collaterals to superficial dorsal horn ar e prominently affected. Axons that run medially in dorsal columns and that give off collaterals to laminae III and IV and the ventral horn a re not demonstrably influenced by treatment with exogenous mNGF. In co ntrast to the striking effects of mNGF on dorsal root axon growth, the influences of hrNT-3 were considerably more complex. Administration o f hrNT-3 increased the mean soma area of DRG neurons, particularly tho se at the larger end of the size spectrum, consistent with its hypothe sized role as a growth factor for proprioceptive sensory neurons. Howe ver, in striking contrast to the actions of mNGF, hrNT-3 consistently inhibited axon collateral growth in gray matter at early developmental stages. At later stages, we could not discern a clear-cut influence o f hrNT-3 on dorsal root axon growth and branching. We conclude that th e ability of mNGF to stimulate axon growth in both white and gray matt er is consistent with the idea that mNGF regulates the developing axon al projections of DRG neurons in vivo. In contrast, systemically admin istered hrNT-3 inhibits the axon collateralizations of DRG neurons in gray matter at early developmental stages. We hypothesize that this in hibitory effect may be related to disruption of a chemotropic gradient of NT-3, or to the widespread expression of the NT-3 receptor trkC, o n non-neuronal cells.