Changes of nerve growth factor synthesis in nonneuronal cells in response to sciatic nerve transection.

Abstract

Abstract. The intact sciatic nerve contains levels of nerve growth factor (NGF) that are comparable to those of densely innervated peripheral target tissues of NGF-responsive (sympathetic and sensory) neurons. There, the high NGF levels are reflected by correspondingly high mRNA N~F levels. In the intact sciatic nerve, mRNA N~F levels were very low, thus indicating that the contribution of locally synthesized NGF by nonneuronal cells is small. However, after transection an increase of up to 15-fold in mRNA NC~ was measured in 4-mm segments collected both proximally and distally to the transection site. Distally to the transection site, augmented mRNA N~F levels occurred in all three 4-mm segments from 6 h to 2 wk after transection, the longest time period investigated. The augmented local NGF synthesis after transection was accompanied by a reexpression of NGF receptors by Schwann cells (NGF receptors normally disappear shortly after birth). Proximal to the transection site, the augmented NGF synthesis was restricted to the very end of the nerve stump that acts as a "substitute target organ" for the regenerating NGF-responsive nerve fibers. While the mRNA NCF levels in the nerve stump correspond to those of a densely innervated peripheral organ, the volume is too small to fully replace the lacking supply from the periphery. This is reflected by the fact that in the more proximal part of the transected sciatic nerve, where mRNA N~F remained unchanged, the NGF levels reached only 40% of control values. In situ hybridization experiments demonstrated that after transection all nonneuronal cells express mRNA NCF and not only those ensheathing the nerve fibers of NGF-responsive neurons. N'ERVE growth factor (NGF)', a well-characterized protein, is essential for the embryonic development and the maintenance of specialized properties of the sympathetic and neural crest-derived sensory neurons (9,23,38). The similarity of the effects resulting from the administration of anti-NGF antibodies and the interference with the retrograde axonal transport provided indirect evidence for NGF to act as a retrograde messenger, transferring information from the peripheral target tissues to the innervating neurons (12, 33). More recently this indirect evidence has been corroborated by the demonstration that while the density of sympathetic innervation of target tissues is correlated with the levels of NGF (18) and its mRNA (14, 34), the high levels of NGF in both sympathetic and sensory ganglia are not reflected by correspondingly high levels of mRNA N~F (5, 14), implying that NGF is accumulated in the ganglia by axonal transport from the periphery rather than by local synthesis. This interpretation was supported by the observation that the destruction of sympathetic nerve terminals by 6-hydroxydopamine or blockade of axonal transport S. Korsching's present address is California Institute of Technology, Division of Biology, 216-76, Pasadena, California 91125.

Trophic Support of Motoneurons: Physiological, Pathophysiological, and Therapeutic Implications

“…Indeed, the local administration of CNTF after transection of the facial nerve in newborn rats virtually completely prevented the degeneration of the motoneuron cell bodies (93). Moreover, in adult animals, in spite of the reduction of the CNTF mRNA after transection of the sciatic nerve, the CNTF -assigned biological activity in the peripheral part of the sciatic nerve undergoing Wallerian degeneration was still about 1000 times higher than the amount of " reactively" enhanced synthesis of NGF by non neuronal sciatic cells 1 week after lesion (35,97,98). Certainly, CNTF is not the sole factor responsible for motoneuron regeneration in peripheral nerves.…”

“…The cloning of CNTF was the prerequisite for producing large quantities of recombinant CNTF (49,59,100) and for the determination of its developmental expression and cellular localization (20,27,86,94,97,100,101). These investigations demonstrated that CNTF is expressed postnatally in myelinating Schwann cells (27,86,97,100,101) and a subpopulation of type I astrocytes (20,101) in the CNS, that CNTF is a cytosolic molecule, and that the biological activity, e.g., in the adult sciatic nerve, is more than 10,000 _ times higher than that of (retrogradely) transported NGF in the rat sciatic nerve (35,97,98).…”

Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input

“…NGF levels were increased (Heumann et al 1987) and NT-3 levels were decreased (Cai et al 1998) following sciatic crush injury. In addition, total neurotrophic support appears to be more important in the survival and maintenance of peripheral neurons than the influence of any one neurotrophin (Zhou et al 1999).…”

Nerve growth factor: Cellular localization and regulation of synthesis

“…This is reflected by the high ratio of NGF to mRNA NGF , in contrast to densely innervated peripheral organs, which bave NGF levels similar to those in the sciatic nerve . Tbe high NGF levels in the sciatic nerve result predominantly from NGF transported retrogradely from peripheral target tissues (Korsching and Thoenen , 1983b;Heumann et al, 1987). However, after transection of the sciatic nerve, local synthesis by nonneuronal cells increases up to 15-fold both proximally and distally to tbe transection site.…”

“…However, the amount of tissue is too small to replace fully the interrupted supply from the periphery. In situ bybridization experiments demonstrated that after transection, all nonneuronal cells expressed mRNA NGF , and not just those ensheathing the NGF-responsive neurons Heumann et al , 1987). When pieces of rat sciatic were brought ioto culture, the mRNA NGF levels first increased to a maximum after 8 hr, and then dropped to lower levels between 12 and 24 hr, just as they do in vivo (Heumann er al.…”