Induction of motor neuron sprouting in vivo by ciliary neurotrophic factor and basic fibroblast growth factor

Abstract

Ciliary neurotrophic factor (CNTF) and basic fibroblast growth factor (bFGF) were tested for effects on sprouting by motor neurons innervating the adult mouse gluteus muscle. Factors were delivered by subcutaneous injection directly over the surface of the superior gluteus muscle once daily for 7 d and then end plates and axons were visualized by combined silver and cholinesterase staining. CNTF (500 ng daily) induced sprouting both from end plates and from the subset of nodes of Ranvier that are closest to the end plate. The effect of CNTF was potentiated twofold by coadministration of bFGF at doses of 2-20 ng daily, whereas treatment with bFGF alone failed to induce sprouting from either end plates or nodes of Ranvier. The sprouting stimulus delivered by the factors showed limited penetrance into the muscle and restricted lateral spread from the injection site.Two types of trauma induce motor neuron sprouting in muscle, partial denervation and paralysis. These induce sprouting both from end plates and from nodes of Ranvier. At least two physiological signals have been proposed to control sprouting (Brown et al., 1981). One is produced by muscle as a consequence of paralysis, and the other is produced within intramuscular nerves due to the presence of degenerating axons.The evidence that muscle is the source of the paralysis-induced signal for sprouting includes the following. First, paralysis of muscle by blockade of axonal conduction with TTX (Brown and Ironton, 1977) blockade ofACh release by botulinum toxin (Duchen, 1970) and blockade of ACh action by a-bungarotoxin (Holland and Brown, 1980) all induce sprouting from motor axon terminals. Since all of these manipulations have only one effect in common, induction of muscle paralysis, paralyzed muscle is likely to be the source of the signal for terminal sprouting. Second, the induction of sprouting by botulinum toxin can be blocked by restoring contractile activity in the paralyzed muscle through direct electrical stimulation (Brown et al., 1980a). Partial denervation also induces sprouting from undamaged motor axon terminals, and this too can be blocked by electrical stimulation (Ironton et al., 1978).The strongest stimulus for nodal sprouting, in contrast, is the presence of degenerating axons (Brown et al., 1980a). Partial denervation induces nodal sprouting from undamaged axons

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

“…Notably, however, the junctions with sprouts were preferentially located near the injection sites, indicating that exposure of the muscle junctions to CNTF had been limited or uneven (data not shown; see Discussion). This had also been noted in a previous analysis of CNTF-treated Gluteus muscles (Gurney et al, 1992). We subsequently found that CNTF subcutaneously applied to LAL, a thin, superficial muscle at the back of the head with well-recognized advantages for pharmacological studies (AngautPetit et al, 1987,Lanuza et al, 2002, could induce nearly all of the nerve terminals to sprout.…”

“…We found that CNTF subcutaneously applied to LG muscles, using the protocol that elicited robust sprouting in LAL muscles, evoked little if any sprouting. Moreover, junctions with sprouts were restricted to the immediate vicinity of the injection sites, suggesting that exposure of LG junctions to CNTF was limited (see also Gurney et al, 1992). In contrast, consistent with the recognized advantages of LAL muscles for pharmacological studies (Angaut-Petit et al, 1987,Lanuza et al, 2002, we observed that CNTF injected between the subdermal connective tissue and the LAL fascia, but not CNTF injected subcutaneously into LG or other hindlimb muscles, formed a local subdermal swelling that persisted for at least one hour before vascular reabsorption (data not shown; cf., Lanuza et al, 2001).…”

“…Several neurotrophic factors, including Ciliary Neurotrophic Factor (CNTF), elicit terminal sprouting when they are administered exogenously to intact muscles (Caroni and Grandes, 1990,Gurney et al, 1992,Caroni et al, 1994,Kwon and Gurney, 1994,Funakoshi et al, 1995,Tarabal et al, 1996,Trachtenberg and Thompson, 1997,Siegel et al, 2000. Although the physiological roles of most of these diffusible factors remain unclear, an earlier genetic analysis of CNTF null (−/−) mice provided evidence for the particular importance of CNTF as a key mediator of the sprouting responses; Siegel et al (2000) reported that paralysis, partial denervation, and exogenous CNTF all failed to elicit significant sprouting in the null mice and concluded that CNTF is required for motor nerve sprouting.…”

Transplanted Mouse Embryonic Stem-Cell-Derived Motoneurons Form Functional Motor Units and Reduce Muscle Atrophy

“…Finally, ES-cell-derived MNs may not be as responsive to sprouting cues as the endogenous neurons. That is, there may be a mismatch between the sprouting cues (perhaps CNTF; (Gurney et al, 1992;Sendtner et al, 1992;Smith et al, 1993) released by Schwann cells and the responsiveness of the ES-cell-derived MNs (Son and Thompson, 1995).…”

Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina

“…To the best of our knowledge we are unaware of reports of such a process in photoreceptor cells, yet, this is not unexpected since CNTF has recently been shown to induce the dedifferentiation of adult human myoblasts into multipotent progenitor cells (Chen et al, 2005), as well as the transformation of striatal astrocytes toward a more immature and activated phenotype (Escartin et al, 2006). CNTF is known to elicit the formation of new neuritic processes in rodent motor neurons and this process is currently being investigated as a potential approach to treat partial denervation and neuromuscular paralysis (Gurney et al, 1992;Siegel et al, 2000). More recently, it was reported that gene delivery of CNTF in a feline model causes neurite extension from rods, bipolar, and horizontal cells, and such a process may be seen as a detrimental effect (Sethi et al, 2005).…”