CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex
ABSTRACT Ciliary neurotrophic factor (CNTF) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, CNTFR, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (LIFR). Striking phenotypic differences between CNTF- and CNTFR-deficient mice suggest that CNTFR serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (CLC) and the soluble receptor cytokine-like factor-1 (CLF). CLF expression was required for CLC secretion, and the complex acted only on cells expressing functional CNTF receptors. The CLF/CLC complex activated gp130, LIFR and signal transducer and activator of transcription 3 (STAT3) and supported motor neuron survival. Our results indicate that the CLF/CLC complex is a second ligand for CNTFR with potentially important implications in nervous system development.
- SourceAvailable from: Andrea Angius
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- "The CRLF1 protein is a member of the ciliary neurotrophic factor receptor (CNTFR; MIM #118946; locus 9p13.3) pathway and interacts with cardiotrophin-like cytokine factor 1 (CLCF1; MIM #607672; locus 11q13.2) to form a stable heterodimeric complex, CRLF1/CLCF1, which belongs to the family of the interleukin-6 (IL-6) cytokine family and acts as a second functional ligand for the CNTF receptor alpha [Elson et al., 2000], composed by gp130 (MIM #600694; locus 5q11.2) and leukemia inhibitory factor receptor beta (LIFR; MIM# 151443; locus 5p13.1). This pathway is known to be important for the development and maintenance of the nervous system and muscles. "
ABSTRACT: Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia associated with death in most cases in the first years of life. To date 24 distinct CRLF1 mutations have been found either in homozygosity or in compound heterozygosity in CS/CISS1 patients, with the highest prevalence in Sardinia, Turkey and Spain. By reporting 11 novel CRLF1 mutations, here we expand the mutational spectrum of CRLF1 in the CS/CISS1 syndrome to a total of 35 variants and present an overview of the different molecular and clinical features of all of them. To catalogue all the 35 mutations we created a CRLF1 mutations database, based on the Leiden Open (source) Variation Database (LOVD) system (https://grenada.lumc.nl/LOVD2/mendelian_genes/variants). Overall, the available functional and clinical data support the fact that both syndromes actually represent manifestations of the same autosomal recessive disorder caused by mutations in the CRLF1 gene. Therefore, we propose to rename the two overlapping entities with the broader term of Crisponi/CISS1 syndrome. This article is protected by copyright. All rights reserved.Human Mutation 02/2014; DOI:10.1002/humu.22522 · 5.05 Impact Factor
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- "cytokine-like factor (CLF). The heterodimer conformation of CLC/CLF is found to be similar to that of IL-12, although both subunits are not linked via a disulphide bridge . The CLC/CLF dimers signal via the CNTF receptor complex. "
ABSTRACT: Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 families, is reported to exhibit a plethora of pleiotropic effects in the heart such as cytoprotective, pro-proliferative and pro-fibrotic ones. An extensive research has been devoted on proliferative and pro-fibrotic effects of CT-1on the heart. Thus the present review has been aimed to critically define the cytoprotective effects of CT-1 and the cellular and molecular mechanisms involved in them. Although a lot many effects of CT-1 have been described on the heart, CT-1has now also been reported to exhibit important protective effects in other organs such as liver, kidney or nervous system. CT-1 produces its effects through a unique receptor system comprising LIF receptor (LIFRβ) and a common signal transducer, the glycoprotein 130 (gp130). The signaling pathway downstream from gp130 is based on at least, three distinct pathways: 1) the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, 2) the p42/44 mitogen-activated protein kinase (p42/44 MAPK) pathway, also known as the extracellular receptor kinase-1/2 (ERK1/2) pathway, and 3) the phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway. Since CT-1 easily achieves its cytoprotective effects via a combination of the above three signaling pathways, it becomes quite necessary to determine which pathway(s) is involved in each particular effect of CT-1. In each of its target organs, CT-1 may also display differential mechanisms of cytoprotection, and thus it is relevant to understand how these mechanisms are locally regulated.Current Medicinal Chemistry 11/2012; 20(2). DOI:10.2174/0929867311320020005 · 3.85 Impact Factor
- "Interestingly, CT-1 is secreted from newly generated neurons, suggesting that astrogliogenesis is triggered in part by the accumulation of CT-1-expressing neurons. Other gp130 family cytokines including NP and the cardiotrophin-like cytokine (CLC; also known as novel neurotrophin 1 and B cell stimulating factor 3), which binds CNTFRa together with cytokine-like factor 1 (CLF1) (Elson et al., 2000), could also have a role in gliogenesis since the gliogenesis phenotype in the CT-1 mice is apparently not as severe as that seen in gp130 or LIFRb KO mice. "
Article: Cytokines and CNS Development[Show abstract] [Hide abstract]
ABSTRACT: Cytokines are pleotrophic proteins that coordinate the host response to infection as well as mediate normal, ongoing signaling between cells of nonimmune tissues, including the nervous system. As a consequence of this dual role, cytokines induced in response to maternal infection or prenatal hypoxia can profoundly impact fetal neurodevelopment. The neurodevelopmental roles of individual cytokine signaling pathways are being elucidated through gain- and loss-of-function studies in cell culture and model organisms. We review this work with a particular emphasis on studies where cytokines, their receptors, or components of their signaling pathways have been altered in vivo. The extensive and diverse requirements for properly regulated cytokine signaling during normal nervous system development revealed by these studies sets the foundation for ongoing and future work aimed at understanding how cytokines induced normally and pathologically during critical stages of fetal development alter nervous system function and behavior later in life.Neuron 10/2009; 64(1):61-78. DOI:10.1016/j.neuron.2009.09.002 · 15.98 Impact Factor