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Ciliary Neurotrophic Factor
(1994)
Interleukin-6, leukemia inhibitory factor, oncostatin M. Interleukin-11, and cilialy neurotrophic factor bind to receptor complexes that share the signal transducer gp130. Upon binding, the ligands rapidly activate DNA binding of acute-phase response factor (APRF), a protein antigenicaly relaled to the p91 subunit of the interferon-stimulated gene factor-(ISGF-3a). These cytokines caused tyrosine phosphorylation of APRF and ISGF-3a p91. Protein kinases of the Jak family were also rapidly tyrosine phosphorylated, and both APRF and Jak1 associated with gp130. These data indicate that Jak family protein kinases may participate in IL-6 signaling and that APRF may be activated in a complex with gp130.
Motoneuron diseases represent a m&jor challenge to modern neurology, yet their clinical manifestations ware first described more than hundred years ago, and despite many studies the etiology of these diseases ramd,ns obscure with no effective treatments having been reported. Although progress has been made in establishing genetic linkage in the rare inherited for.ms of these diseases such as familial amyotrophic lateral scleriosisl , spinal mDscular atrophy and X-linked bulbo-spinal-mDscular atrophy, this new information has not yet affected therapeutic techniques. During the last few years several important steps have been taken concerning the physiological mechanisms involved in motoneuron survival during development, after lesion and in animal models of degenerative diseases, the molecular clOning of several new neurotrophic factors (brain-derived neurotrophic factor (BDNP), neurotrophin-3 and-4 (NT-3 and NT-4) and ciliary neurotrophic factor (CNTP)); the identification of a gene family of receptor molecules for same of these factors, progress in the understanding of the effects of polypeptide growth factors on muscle cell differentiation, neuronal sprouting (insulin-like growth factor-I and -11 (IGF-I and IGF-II), and in vitro motoneuronal survival (CNTF, IGF-I and -II and basic FGF). These findings have raised new hopes in that they could lead to a better understanding of the pathophysiological processes underlying these diseases, and that the pharmacological use of same of these newly characterized neurotrophic factors could present new possibilities for the treatment of these diseases.
CNTF is a cytosolic molecule expressed postnatally in myelinating Schwann cells and in a subpopulation of astrocytes. Although CNTF administration prevents lesion-mediated and genetically determined motor neuron degeneration, its physiological function remained elusive. Here it is reported that abolition of CNTF gene expression by homologous recombination results in a progressive atrophy and loss of motor neurons in adult mice, which is functionally reflected by a small but significant reduction in muscle strength.
The structure of the rat ciliary neurotrophic factor (CNTF) gene and the regulation ofCNTF mRNA levels in cultured glial cells were investigated. The rat mRNA is encoded by a simple two-exon transcription unit. Sequence analysis of the region upstream of the transcription start-site did not reveal a typical TATA-box consensus sequence. Low levels of CNTF mRNA were detected in cultured Schwann cells, and CNTF mRNA was not increased by a variety of treatments. Three-week-old astrocyteenriched cell cultures from new-born rat brain contained easily detectable CNTF mRNA. In astrocyte-enriched cultures, upregulation of CNTF mRNA levels was observed after treatment with IFN-gamma. CNTF mRNA levels were down-regulated in these cells by treatments that elevate intracellular cyclic AMP and by members of the fibroblast growth factor (FGF) family. The implications of these results for potential in vivo functions of CNTF are discussed.
We 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.
Motoneurons played an essential role in establishing the concept of target-mediated support of innervating neurons. However, it took several decades until molecules were identined which trophically support motoneurons in vitro and in vivo. The most potent molecule identined so far is ciliary neurotrophic factor (CNTF). It is expressed as a cytosolic molecule in myelinating Schwann cells rather than in skeletal muscle in the postnatal period and therefore does not qualify as a target-derived neurotrophic factor regulating motoneuron survival during embryonic development. However, the inactivation of CNTF by gene targeting experiments results in progressive atrophy and degeneration of motoneurons, demonstrating that CNTF plays an essential role as a maintenance factor for motoneurons postnatally. Secretory molecules which are expressed in skeletal muscle during embryonic development and which support motoneurons in culture and partially also in vivo include members of the NGF gene family (BDNF, NT-3, NT-4/S) , FGF-S, IGF-I, and UF. The evaluation of the physiological importance of these molecules is under investigation.