Alternative titles; symbols
HGNC Approved Gene Symbol: CTF1
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38): 16:30,895,846-30,903,560 (from NCBI)
Heart failure is a leading cause of mortality worldwide. A hallmark of the disease is dilated cardiac hypertrophy, which is accompanied by a reactivation of genes expressed in fetal heart development. Reasoning that fetal or embryonic growth factors may mediate the onset of cardiac hypertrophy, Pennica et al. (1995) coupled expression cloning with an embryonic stem cell-based model of cardiogenesis to isolate a 21.5-kD protein, cardiotrophin-1, that potently induces cardiac myocyte hypertrophy in vitro. Amino acid similarity data indicated that CT1 is a member of the family of cytokines that includes leukemia inhibitory factor (LIF; 159540), ciliary neurotrophic factor (CNTF; 118945), oncostatin M (OSM; 165095), interleukin-6 (IL6; 147620), and interleukin-11 (IL11; 147681). Several members of this family that are known to signal through the transmembrane protein gp130 (IL6ST; 600694) stimulate cardiac myocyte hypertrophy, like cardiotrophin-1, suggesting that the gp130 signaling pathway may play a role in cardiac hypertrophy. The 1.4-kb CT1 mRNA is present in the heart and several other mouse tissues.
By screening a heart cDNA library with a mouse Ct1 probe, Pennica et al. (1996) isolated a cDNA encoding human CTF1. The deduced CTF1 protein contains 201 amino acids and shares 80% amino acid identity with the 203-amino acid mouse Ct1 sequence; however, unlike the mouse protein, CTF1 has 2 rather than 1 cys and has no N-glycosylation site. Although other gp130-signaling cytokines have similar structures with 4 alpha helices, they share only 14 to 23% identity with CTF1. Despite lacking a signal sequence, secreted CTF1 and mouse Ct1 induce cardiac myocyte hypertrophy in cell culture and bind to both mouse and human LIFR (151443) but not to OSMR (601743). Northern blot analysis detected a 1.7-kb CTF1 transcript at high levels in heart, skeletal muscle, prostate, and ovary. Low levels were detected in lung, kidney, pancreas, thymus, testis, and small intestine, with little or no expression detected in brain, placenta, spleen, colon, and peripheral blood leukocytes. Pennica et al. (1996) also observed strong expression in fetal lung and kidney.
Pennica et al. (1996) determined by genomic analysis that the CTF1 gene contains 3 exons and spans over 6 to 7 kb.
Using in situ hybridization and RT-PCR, Pennica et al. (1996) detected mouse Ctf1 expression in embryonic limb bud at high levels during motoneuron death and markedly reduced after the period of motoneuron cell death. Pennica et al. (1996) concluded that Ctf1 expression is consistent with a role for Ctf1 in regulating motoneuron numbers during development. Western blot analysis demonstrated that myotubes in culture secrete a Ctf1 gene product with an apparent molecular weight of 30 kD.
Using a purified motoneuron culture system, Pennica et al. (1996) demonstrated that Ctf1 is a potent long-term survival factor for a fraction of motoneurons similar to those kept alive in culture by CNTF or LIF. The authors also demonstrated that Ctf1 keeps lesioned motoneurons alive in vivo after neonatal axotomy. They observed a reduction in Ctf1-dependent motoneuron survival in culture upon treatment with phosphatidylinositol-specific phospholipase C (see 600220). Because phospholipase C can specifically cleave the GPI linkage that attaches certain molecules to the cell surface, Pennica et al. (1996) hypothesized that the Ctf1 receptor, like the CNTFR (118946), has an essential GPI-linked component. Several methods were unable to detect binding of Ctf1 to GPI-linked CNTFR alpha-subunit and hypothesized that the GPI-linked component of the Ctf1 receptor complex on motoneurons may therefore be a novel cytokine receptor subunit. Pennica et al. (1996) hypothesized that Ctf1 may be important in normal motoneuron development and as a potential tool for slowing motoneuron degeneration in human diseases.
Development of the cerebral cortex is achieved through a common pool of precursor cells that sequentially generate neurons and glial cells. Barnabe-Heider et al. (2005) demonstrated that murine cortical neurons synthesized and secreted cardiotrophin-1, which acted as gliotrophic factor and activated the gp130-JAK (147795)-STAT (102582) pathway. Secretion of Ctf1 was essential for the timed genesis of astrocytes as shown in vitro and in vivo. The findings described a neural feedback mechanism ensuring that gliogenesis does not occur until neurogenesis is largely complete.
By FISH and radiation hybrid analysis, Pennica et al. (1996) mapped the CTF1 gene to 16p11.2-p11.1, a location distinct from other IL6 cytokine family members.
Derouet et al. (2004) determined that the mouse Ctf1 gene maps to chromosome 7F3 in tandem with the neuropoietin gene (Np). The authors suggested that Ctf1 and Np arose from a gene duplication event. In human, NP has evolved into a pseudogene.
Amyotrophic lateral sclerosis (ALS; 105400) is a mainly sporadic neurodegenerative disorder characterized by loss of cortical and spinal motoneurons. Some familial ALS (FALS) cases have been linked to dominant mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1; 147450). Transgenic mice overexpressing a mutated form of human SOD1 with a gly93-to-ala substitution (147450.0008) develop progressive muscle wasting and paralysis as a result of spinal motoneuron loss and die at 5 to 6 months. Bordet et al. (2001) investigated the effects of neurotrophic factor gene delivery in this FALS model. Intramuscular injection of an adenoviral vector encoding CTF1 in SOD1(G93A) newborn mice delayed the onset of motor impairment as assessed in the rotarod test. By CTF1 treatment, axonal degeneration was slowed, skeletal muscle atrophy was largely reduced, and the time-course of motor impairment was significantly decreased.
Spinal muscular atrophy (SMA1; 253300) is an autosomal recessive disorder characterized by degeneration of lower motor neurons caused by mutations of the survival motor neuron gene (SMN1; 600354). Conditionally mutant mice homozygous for a deletion of Smn exon 7 (directed to neurons) display skeletal muscle denervation, moderate loss of motor neuron cell bodies, and severe axonal degeneration. Lesbordes et al. (2003) reported therapeutic benefits of systemic delivery of CTF1. Intramuscular injection of adenoviral vector expressing CTF1, even at very low dose, improved median survival, delayed motor defect, and exerted a protective effect against loss of proximal motor axons and aberrant cytoskeletal organization of motor synaptic terminals. In spite of the severity of the SMA phenotype in mutant mice, CTF1 was able to slow disease progression.
Barnabe-Heider, F., Wasylnka, J. A., Fernandes, K. J. L., Porsche, C., Sendtner, M., Kaplan, D. R., Miller, F. D. Evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardiotrophin-1. Neuron 48: 253-265, 2005. [PubMed: 16242406] [Full Text: https://doi.org/10.1016/j.neuron.2005.08.037]
Bordet, T., Lesbordes, J.-C., Rouhani, S., Castelnau-Ptakhine, L., Schmalbruch, H., Haase, G., Kahn, A. Protective effects of cardiotrophin-1 adenoviral gene transfer on neuromuscular degeneration in transgenic ALS mice. Hum. Molec. Genet. 10: 1925-1933, 2001. [PubMed: 11555629] [Full Text: https://doi.org/10.1093/hmg/10.18.1925]
Derouet, D., Rousseau, F., Alfonsi, F., Froger, J., Hermann, J., Barbier, F., Perret, D., Diveu, C., Guillet, C., Preisser, L., Dumont, A., Barbado, M., Morel, A., deLapeyriere, O., Gascan, H., Chevalier, S. Neuropoietin, a new IL-6-related cytokine signaling through the ciliary neurotrophic factor receptor. Proc. Nat. Acad. Sci. 101: 4827-4832, 2004. [PubMed: 15051883] [Full Text: https://doi.org/10.1073/pnas.0306178101]
Lesbordes, J.-C., Cifuentes-Diaz, C., Miroglio, A., Joshi, V., Bordet, T., Kahn, A., Melki, J. Therapeutic benefits of cardiotrophin-1 gene transfer in a mouse model of spinal muscular atrophy. Hum. Molec. Genet. 12: 1233-1239, 2003. [PubMed: 12761038] [Full Text: https://doi.org/10.1093/hmg/ddg143]
Pennica, D., Arce, V., Swanson, T. A., Vejsada, R., Pollock, R. A., Armanini, M., Dudley, K., Phillips, H. S.., Rosenthal, A., Kato, A. C., Henderson, C. E. Cardiotrophin-1, a cytokine present in embryonic muscle, supports long-term survival of spinal motoneurons. Neuron 17: 63-74, 1996. [PubMed: 8755479] [Full Text: https://doi.org/10.1016/s0896-6273(00)80281-0]
Pennica, D., King, K. L., Shaw, K. J., Luis, E., Rullamas, J., Luoh, S.-M., Darbonne, W. C., Knutzon, D. S., Yen, R., Chien, K. R., Baker, J. B., Wood, W. I. Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc. Nat. Acad. Sci. 92: 1142-1146, 1995. [PubMed: 7862649] [Full Text: https://doi.org/10.1073/pnas.92.4.1142]
Pennica, D., Swanson, T. A., Shaw, K. J., Kuang, W.-J., Gray, C. L., Beatty, B. G., Wood, W. I. Human cardiotrophin-1: protein and gene structure, biological and binding activities, and chromosomal localization. Cytokine 8: 183-189, 1996. [PubMed: 8833032] [Full Text: https://doi.org/10.1006/cyto.1996.0026]