Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration.

Abstract

Abstract. Ciliary neurotrophic factor (CNTF) is expressed in high quantifies in Schwann cells of peripheral nerves during postnatal development of the rat. The absence of a hydrophobic leader sequence and the immunohistochemical localization of CNTF within the cytoplasm of these cells indicate that the factor might not be available to responsive neurons under physiological conditions. However, CNTF supports the survival of a variety of embryonic neurons, including spinal motoneurons in culture. Moreover we have recently demonstrated that the exogenous application of CNTF protein to the lesioned facial nerve of the newborn rat rescued these motoneurons from cell death. These results indicate that CNTF might indeed play a major role in assisting the survival of lesioned neurons in the adult peripheral nervous system. Here we demonstrate that the CNTF mRNA and protein levels and the manner in which they are regulated are compatible with such a function in lesioned peripheral neurons. In particular, immunohistochemical analysis showed significant quantities of CNTF at extracellular sites after sciatic nerve lesion. Western blots and determination of CNTF biological activity of the same nerve segments indicate that extracellular CNTF seems to be biologically active. After nerve lesion CNTF mRNA levels were reduced to <5 % in distal regions of the sciatic nerve whereas CNTF bioactivity decreased to only one third of the original before-lesion levels. A gradual reincrease in Schwann cells occurred concomitant with regeneration.

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.…”

“…That CNTF has a direct action on motoneurons could be deduced from the fact that the survival effect in single motoneuron cultures was identical to that in 80% pure low-density cultures (94) . 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).…”

Genes and the ageing muscle: a review on genetic association studies

“…Although CNTF synthesis is associated with peripheral nerves (Sendtner et al 1992), a specific binding subunit of the CNTF receptor (CNTF receptor-α), abundantly expressed in skeletal muscle , is required for CNTF activity ). In addition, CNTF levels decline with age, and exogenous CNTF administration in older rats increases muscular strength (Guillet et al 1999).…”

Ciliary neurotrophic factor is not required for terminal sprouting and compensatory reinnervation of neuromuscular synapses: Re-evaluation of CNTF null mice

“…To label Schwann cells in denervated muscles, we used S100 antibody in combination with an antibody to p75 (Chemicon, Billerica, MA). Endogenous CNTF was labeled with a rabbit polyclonal antibody to CNTF (Sendtner et al, 1992). To determine CNTF immunoreactivity in denervated tSCs with simultaneous labeling of axons, SCs and AChRs, we used the Kosmos mouse line in which Schwann cells are genetically labeled with eGFP (Zuo et al, 2004).…”

“…Indeed, tSCs become reactive in response to paralysis or denervation (Reynolds and Woolf, 1992), and extend processes that appear to induce and guide terminal sprouts from innervated-to denervated muscle fibers (Son and Thompson, 1995a,Ko and Chen, 1996,Lubischer and Thompson, 1999,O'Malley et al, 1999,Love et al, 2003,Tam and Gordon, 2003b. Schwann cells are also the only cells in the peripheral nervous system that are known to express CNTF (Stockli et al, 1989,Friedman et al, 1992,Rende et al, 1992,Sendtner et al, 1992. We therefore were attracted by the possibility that nerve terminals in CNTF−/− mice fail to sprout because tSCs fail to extend processes.…”