HGNC Approved Gene Symbol: CNTF
Cytogenetic location: 11q12.1 Genomic coordinates (GRCh38): 11:58,622,665-58,625,733 (from NCBI)
CNTF was purified to homogeneity from rat and rabbit sciatic nerve, enabling the isolation of cDNAs encoding the factor. Based on the cDNA sequences, Lam et al. (1991) designed synthetic oligonucleotide probes which were used in the isolation of the human CNTF gene. They described the amino acid sequence of human CNTF as well as the organization of the gene. The human protein showed approximately 85% identity with CNTF of rat and rabbit.
By analysis of human-hamster somatic cell hybrids, Lam et al. (1991) mapped the CNTF gene to chromosome 11. Using a rodent/human somatic cell DNA mapping panel and fluorescence in situ hybridization, Lev et al. (1993) localized the CNTF gene to the proximal region of 11q. In addition, they identified a polymorphic tandem CA/GT dinucleotide repeat associated with the human CNTF gene.
To sublocalize the CNTF gene on chromosome 11, Giovannini et al. (1993) isolated cosmid clones containing the gene by use of a chromosome 11-specific library. Using these clones in fluorescence in situ hybridization, they found that the gene maps at an FLpter of 0.46, corresponding to a cytogenetic band position of 11q12.2, according to the method of Lichter et al. (1990). Yokoji et al. (1995) isolated a full-length cDNA for human ciliary neurotrophic factor from a sciatic nerve cDNA library, determined its structure, and localized it to chromosome 11q12 by fluorescence in situ hybridization.
Kaupmann et al. (1991) demonstrated that the mouse Cntf gene is on mouse chromosome 19 and that its expression is unaffected in the mouse neurologic mutant wobbler (see 614633), a form of spinal muscular atrophy.
Barbin et al. (1984) described the neurotrophic activity of ciliary neurotrophic factor purified from chick eye employing a survival assay for neurons from chick embryonic ciliary ganglia. In addition to neurotrophic effects on parasympathetic neurons, CNTF was shown to have activities on sympathetic and sensory neurons.
Homozygous pmn/pmn mice have a progressive motor neuronopathy which becomes evident in the hindlimbs at the end of the third postnatal week; all the mice die of respiratory paralysis 6 or 7 weeks after birth. Sendtner et al. (1992) found that treatment with ciliary neurotrophic factor prolonged survival and greatly improved motor function in these mice and reduced the morphologic manifestations of the neural degeneration, even though treatment did not start until the first symptoms of disease had become apparent and substantial degenerative changes were already present. Because CNTF has a short half-life and because pmn mice do not tolerate daily injections of CNTF and are too small to accommodate infusion pumps, the agent was delivered by intraperitoneal injection of a mouse cell line transfected with a genomic construct that releases high quantities of biologically active CNTF. The mode of action is not known. The CNTF and the CNTF-processing pathways are not perturbed in pmn. Furthermore, CNTF appears not to be involved in motor neuron survival during development.
Masu et al. (1993) extended our understanding of the physiologic function of CNTF. They abolished CNTF gene expression by homologous recombination in mice and found that progressive atrophy and loss of motor neurons occurred in adult mice, accompanied by a small but significant reduction in muscle strength. The authors stated that these studies demonstrated that expression of the gene is not necessary for the development of spinal motor neurons as assessed by morphologic criteria, but that it is essential for maintenance of function in motor neurons in the postnatal period.
Receptor subunits for CNTF share sequence similarity with the leptin receptor (LEPR; 601007). Gloaguen et al. (1997) reported that CNTF and leptin (LEP; 164160) activate a similar pattern of STAT factors in neuronal cells (see STAT3; 102582), and that mRNAs for CNTF receptor subunits, similarly to the mRNA of LEPR, are localized in mouse hypothalamic nuclei involved in the regulation of energy balance. Systemic administration of CNTF or LEP to ob/ob mice, which lack functional leptin, led to rapid induction of the tis-11 primary response gene (190700) in the arcuate nucleus, suggesting that both cytokines can signal to the hypothalamic satiety centers. Consistent with this idea, CNTF treatment of ob/ob mice was found to reduce the adiposity, hyperphagia, and hyperinsulinemia associated with leptin deficiency. Unlike leptin, CNTF also reduced obesity-related phenotypes in db/db mice, which lack a functional leptin receptor, and in mice with diet-induced obesity, which are partially resistant to the actions of leptin. Gloaguen et al. (1997) suggested that identification of a cytokine-mediated anti-obesity mechanism that acts independently of the leptin system may help development of strategies for treatment of obesity associated with leptin resistance.
Emerich et al. (1997) evaluated whether CNTF is a neuroprotective agent in a nonhuman primate model of Huntington disease (HD; 143100). Emerich et al. (1997) gave cynomolgus monkeys intrastriatal implants of polymer-encapsulated baby hamster kidney fibroblasts that had been genetically modified to secrete human CNTF. One week later, monkeys received unilateral injections of quinolinic acid into the previously implanted striatum to reproduce the neuropathology seen in HD. Human CNTF exerted a neuroprotective effect on several populations of striatal cells, including GABAergic, cholinergic, and diaphorase-positive neurons, which were all destined to die following administration of quinolinic acid. Human CNTF also prevented the retrograde atrophy of layer V neurons in motor cortex and exerted a significant protective effect on the GABAergic innervation of the globus pallidus and pars reticulata of the substantia nigra, the 2 important target fields of the striatal output neurons. Emerich et al. (1997) concluded that human CNTF has a trophic influence on degenerating striatal neurons as well as on critical nonstriatal regions such as the cerebral cortex, supporting the idea that human CNTF may help to prevent the degeneration of vulnerable striatal populations and cortical-striatal basal ganglia circuits in Huntington disease.
CNTF was first characterized as a trophic factor for motor neurons in the ciliary ganglion and spinal cord, leading to its evaluation in humans suffering from motor neuron disease. In these trials, CNTF caused unexpected and substantial weight loss, raising concerns that it might produce cachectic-like effects. Countering this possibility was the suggestion that CNTF was working via a leptin-like mechanism to cause weight loss, based on the findings that CNTF acts via receptors that are not only related to leptin receptors, but are also similarly distributed within hypothalamic nuclei involved in feeding. However, although CNTF mimics the ability of leptin to cause fat loss in mice that are obese because of genetic deficiency of leptin (ob/ob mice), CNTF is also effective in diet-induced obesity models that are more representative of human obesity and which are resistant to leptin. This discordance again raised the possibility that CNTF might be acting via nonleptin pathways, perhaps more analogous to those activated by cachectic cytokines. Arguing strongly against this possibility were the findings of Lambert et al. (2001), who showed that CNTF can activate hypothalamic leptin-like pathways in diet-induced obesity models unresponsive to leptin, that CNTF improves prediabetic parameters in these models, and that CNTF acts very differently than the prototypic cachectic cytokine interleukin-1 (IL1; 147760). Further analyses of hypothalamic signaling revealed that CNTF can suppress food intake without triggering hunger signals or associated stress responses that are otherwise associated with food deprivation; thus, unlike forced dieting, cessation of CNTF treatment does not result in binge overeating and immediate rebound weight gain. The hope was expressed that the ongoing clinical studies of a CNTF peptide would confirm that it can produce substantial weight loss in obese human patients at doses that are well tolerated.
In rodent cortical progenitor cells that differentiate into astrocytes, Song and Ghosh (2004) found that fibroblast growth factor-2 (FGF2; 134920) regulates the ability of CNTF to induce expression of glial fibrillary acidic protein (GFAP; 137780), an astrocyte-specific gene. FGF2 facilitates access of the signal transducer and activator of transcription (STAT)/CRE-binding protein (CBP) complex to the GFAP promoter by inducing lys4 methylation and suppressing lys9 methylation of histone H3 at the STAT binding site. Thus, astrocyte differentiation involves a switch in chromatin state at a specific site, representing epigenetic regulation.
Kokoeva et al. (2005) demonstrated that centrally administered CNTF induces cell proliferation and feeding centers of the murine hypothalamus. Many of the newborn cells expressed neuronal markers and showed functional phenotypes relevant for energy balance control, including the capacity for leptin (164160)-induced phosphorylation of STAT3 (102582). Coadministration of the mitotic blocker Ara-C eliminated the proliferation of neural cells and abrogated the long-term, but not the short-term, effect of CNTF on body weight. Kokoeva et al. (2005) concluded that their findings link the sustained effect of CNTF on energy balance to hypothalamic neurogenesis.
Using in situ peroxidase and immunofluorescence staining in mouse hearts, Raju et al. (2006) localized Cntf receptors to the sarcolemma and confirmed the localization by immunoblot on isolated myocytes. Subcutaneous administration of recombinant CNTF in ob/ob and db/db mice resulted in significant reductions in cardiac hypertrophy. Western blotting showed that both leptin and CNTF activated STAT3 and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) pathways in cultured adult mouse cardiomyocytes and cardiac tissue from ob/ob and db/db mice. Raju et al. (2006) concluded that CNTF plays a role in a cardiac signal transduction pathway that regulates obesity-related left ventricular hypertrophy.
CNTF is a major mediator of the protective effects of Schwann cells, both under physiologic and pathologic conditions. Ito et al. (2006) identified SOX10 (602229) as a key regulator of CNTF expression. Sox10 overexpression in cultured primary Schwann cells from rat sciatic nerves upregulated Cntf protein levels more than 100-fold. In addition, Cntf expression was significantly lower in sciatic nerves of Sox10 +/- mice, suggesting that SOX10 acts as a physiologic regulator of CNTF gene expression in vivo.
In isolated mouse skeletal muscle and in vivo experiments, Watt et al. (2006) demonstrated that Cntf signals through the Cntfr-alpha/Il6r (147880)/Gp130-beta (600694) receptor complex to increase fatty acid oxidation and reduce insulin resistance in skeletal muscle by activating AMPK (see 602739), independent of signaling through the brain. These peripheral effects were not suppressed in diet-induced or genetic mouse models of obesity.
Takahashi et al. (1994) identified a mutation in the CNTF gene (118945.0001) that caused aberrant RNA splicing and abolished expression of the CNTF protein. They calculated that approximately 2.3% of the Japanese population are homozygous for this null mutation. CNTF deficiency did not appear to be associated with any neurologic dysfunction. Takahashi et al. (1994) noted that CNTF lacks a signal peptide and is found stored inside adult glial cells, perhaps awaiting release by some mechanism induced by injury. They suggested that CNTF may act in response to injury or other stresses and not be essential during development.
Giess et al. (2002) described a 25-year-old male patient who died from familial amyotrophic lateral sclerosis (ALS; 105400) after a rapid disease course of only 11 months. Sequencing of the SOD1 gene (147450) revealed a heterozygous missense mutation. The same mutation was found in both his healthy 35-year-old sister and his mother, who did not develop the disease until age 54 years. Two of her sisters had died from ALS at 56 and 43 years of age. The maternal grandmother and a great-grandmother had died from progressive muscle weakness and atrophy at ages 62 and less than 50 years, respectively. Giess et al. (2002) screened for candidate modifier genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient and found an additional homozygous mutation in CNTF (118945.0001) that was not found in his as yet unaffected sister. The authors found that the SOD1 model of ALS when present in Cntf-deficient mice is associated with development of motoneuron disease at a significantly earlier stage than in transgenic Sod1 mice that were wildtype for CNTF. Linkage analysis in mice revealed that the SOD1 gene was solely responsible for the disease; however, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic ALS who had a homozygous CNTF gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, Giess et al. (2002) concluded that CNTF acts as a modifier gene that leads to early onset of disease in patients with familial ALS who have SOD1 mutations, in patients with sporadic ALS, and in the hSOD1G93A mouse model.
Among 400 patients with ALS (351 with sporadic ALS and 49 with familial ALS and a homozygous mutation in the SOD1 gene) and 236 controls, Al-Chalabi et al. (2003) found no difference in age of onset, clinical presentation, rate of progression, or disease duration for those with 1 or 2 copies of the null allele (118945.0001), suggesting that CNTF is not a major disease modifier in ALS.
Proximal spinal muscular atrophy (SMA) is caused by homozygous loss or mutation of the SMN1 (601627) gene on human chromosome 5. In patients with milder forms of the disease who normally reach adulthood, enlargement of motor units is regularly observed. Simon et al. (2010) analyzed Smn +/- mice, a model of type III/IV SMA, electrophysiologically and histologically to characterize single motor units. Smn +/- mice exhibit progressive loss of motor neurons and denervation of motor endplates starting at 4 weeks of age. Confocal analysis revealed pronounced sprouting of innervating motor axons. As CNTF is highly expressed in Schwann cells, Simon et al. (2010) investigated its role in a compensatory sprouting response and maintenance of muscle strength in this mouse model. Genetic ablation of CNTF resulted in reduced sprouting and decline of muscle strength in Smn +/- mice. The authors concluded that CNTF may be necessary for a sprouting response and thus may enhance the size of motor units in skeletal muscles of Smn +/- mice.
Takahashi et al. (1994) identified an apparent polymorphism of the CNTF gene. An acceptor splice site mutation caused aberrant mRNA splicing and abolished expression of CNTF protein. The specific change was a G-to-A transition at position -6 of the acceptor splice site leading to insertion of 4 additional ribonucleotides at the beginning of the next exon. This caused a frameshift from amino acid 39, resulting in a stop codon 24 amino acids downstream. (The normal open reading frame codes for 200 amino acids.) The aberrant mRNA was predicted to code for a truncated protein of 62 amino acids. Analysis of tissue samples and transfection of CNTF minigenes into cultured cells demonstrated to Takahashi et al. (1994) that the mutated allele expressed only the mutated mRNA species. Studies with an antiserum that recognized both the normal and mutated CNTF showed complete lack of CNTF immunoreactivity in peripheral nerve tissue from a homozygous mutant subject. In 391 Japanese people tested, 61.9% were normal homozygotes, 39.8% heterozygotes, and 2.3% mutant homozygotes. The distribution of the 3 genotypes were similar in healthy and neurologic disease subjects, indicating that human CNTF deficiency is not causally related to neurologic diseases.
Gelernter et al. (1997) could find no association of the CNTF null allele with unipolar affective disorder, schizophrenia, or Alzheimer disease.
Giess et al. (2002) found this mutation, in addition to a heterozygous missense mutation in the SOD1 gene (147450), in a 25-year-old male patient who died from familial amyotrophic lateral sclerosis (ALS; 105400) after a rapid disease course of only 11 months. The authors demonstrated that CNTF acts as a modifier gene that leads to early onset of disease in patients with familial ALS who have SOD1 mutations, in patients with sporadic ALS, and in the hSOD1G93A mouse model.
In 7 of 288 patients with multiple sclerosis (126200), Giess et al. (2002) identified homozygosity for the CNTF null mutation. The 7 patients demonstrated a significantly earlier age of onset of disease (17 years) compared to patients carrying at least 1 functional CNTF allele (27 years). Six of the 7 patients with the null allele (85%) had marked motor or brainstem symptoms and incomplete remission, which was detected in only 21% of the other patients with MS. Giess et al. (2002) noted that the null allele is very rare, and that the frequency of the homozygous null allele in this group is the same as in control groups, thus indicating that the genotype itself is not a risk factor for development of MS. However, they suggested that trophic support of neurons and oligodendrocytes by CNTF may be critical to reduce early damage caused by inflammatory mediators, and that lack of functional CNTF may lead to earlier onset of clinical symptoms in MS.
O'Dell et al. (2002) genotyped 965 healthy Caucasians, aged 59 to 73 years, for the G-to-A null mutation. The AA genotype was associated with a 10-kg increase in weight (p = 0.03) and 3 kg/m2 greater BMI (p = 0.02) in the 575 men, whereas no effect was found in the 390 women. O'Dell et al. (2002) concluded that the CNTF null mutation confers a moderate effect on obesity in males with the AA genotype, who represent 1% of the general population.
In an analysis of 2 cohorts totaling 755 Caucasian adults, Jacob et al. (2004) found no significant association between CNTF genotype and body weight or BMI. A third combined analysis on a subgroup of subjects matching the O'Dell et al. (2002) cohort on age yielded similar results. Jacob et al. (2004) also found no significant association between CNTF genotype and total body fat or fat-free mass in the 422 members of the cohort in which those parameters were measured.
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