Evidence that fibroblast growth factor 5 is a major muscle-derived survival factor for cultured spinal motoneurons

Abstract

SummaryWe examined the potential role of fibroblast growth factor 5 (FGF-5) as a target-derived trophic factor for spinal motoneurons. Northern analysis of total RNA from rat skeletal muscle revealed an FGF-5 mRNA transcript both during the period of embryonic motoneuron death and in the adult. Recombinant human FGF-5 supported the survival of highly enriched cultures of embryonic chick motoneurons. Significant proportions of the motoneuron survival activity of rat skeletal muscle extracts could be immunoprecipitated using an antiserum to FGF-5. The immunoprecipitable activity was present in soluble and matrix-bound forms in embryonic muscle, but bound exclusively to the extracellular matrix in adult muscle. These results, along with the secretory nature of FGF-5, suggest that FGF-5 may act as a target-derived trophic factor for motoneurons.

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

“…Of particular interest is the complete discrepancy between the effects of FGFs (both bFGF and FGF-5) in vitro and in vivo (3,38,39,70,76) . For example, in contrast to the strong survival effects in vitro (both in chick and rat motoneuron cultures), both molecules were without protective effect against motoneuron degeneration after lesioning of the newborn rat facial nerve (39).…”

“…However, another member of the FGF gene family, FGF -5, seems to fulfill the prerequisites for a target-derived trophic factor for motoneurons. FGF -5 shows a potent survival effect on both chick and rat motoneurons (38,39). It is expressed in rat skeletal muscle from E15 to adulthood.…”

“…Using an antiserum raised against a peptide from the C-terminus of FGF -5, which was able to precipitate recombinant FGF -5, 40-50% of the survival activity present in embryonic rat skeletal muscle extract could be immunoprecipitated. In adult rat skeletal muscle the FGF -5-assigned survival activity was strongly matrix-bound and could only be released by high salt and EDTA (38). The relative contribution of FGF -5 to the survival effect of rat skeletal muscle extract should be judged with caution, as cultured chick embryonic motoneurons were used as an assay, and these cultures do not respond to any of the neurotrophins tested so far (3) (see below).…”

“…The fact that there are distinct discrepancies between the in vitro and in vivo effects of neurotrophic molecules, particularly the lack of effect of all members of the FGF gene family in vivo (39,70,76) compared to their efficacy in vitro (3,38,39), raises the question of whether these molecules would need to be administered as a complex with an appropriate heparan sulfate glycoprotein (71,72) or whether better effects could be obtained by the direct local administration, e.g., by direct gene transfer into the muscle (85), by engineering of (autologous) myoblasts in culture and their reimplantation, or by the use of viral systems (see 66). The approaches delineated here for the gene transfer into skeletal muscle could also be used for the local administration in peripheral nerves, such as the use of engineered autologous Schwann cells, and also in the spinal cord, as an alternative to the intrathecal infusion of neurotrophic molecules.…”

“…Progress was predominantly determined by an improvement of the motoneuron cell culture procedures (3,10,12,33,34,39) and the identification of neurotrophic molecules in adult and/or embryonic skeletal muscles with already known neurotrophic actions on other populations of neurons in vitro and in vivo (3,13,34,36,38,39,45,54,58,80). The importance of appropriate culture systems for motoneurons is demonstrated by the fact that, for a long time, no single, defined molecule could be demonstrated to have a convincing trophic action on motoneurons.…”