Mini reviewCardiotrophin-like cytokine factor 1 (CLCF1) and neuropoietin (NP) signalling and their roles in development, adulthood, cancer and degenerative disorders
Section snippets
Introduction and clarification of terminology
Cardiotrophin-like-cytokine (CLCF1) and neuropoietin (NP) are the least defined of the four-helix bundle cytokines that signal through the gp130 receptor subunit. Until 10 years ago their main roles were thought to be restricted to the regulation of motor neuron development. However, more recent work has identified potential activities in adult biology, degenerative conditions and cancer, in a wide range of organ systems. In this review, I will describe what is currently known about the
Complex formation and signalling pathways activated by CLCF1 and NP
Like other members of the IL-6 family, it is generally understood that the CLCF1 compound cytokines and NP signal by similar mechanisms, involving the use of an α receptor subunit; in this case, ciliary neurotrophic receptor – CNTFR [1], [4]. Although CLCF1, NP and ciliary neurotrophic factor (CNTF) itself share only 16–25% total sequence homology, all three cytokines contain a highly conserved tryptophan hotspot (site 1) that enables binding to the same location on CNTFR [5]. The resulting
Effects of CLCF1/CRLF1 mutations in humans
CRLF1 (CRLF1) and CLCF1 (CLCF1) gene mutations in humans both lead to a variety of syndromes that include “cold-induced sweating” (CISS – profuse sweating after exposure to cold), suckling problems during infancy and feeding difficulties in adult life, as well as musculoskeletal abnormalities including spinal kyphoscoliosis, contracture of the muscles around the elbows, palatal and frontonasal malformations [27], [28]. Since human mutations in CNTF are common, but are not associated with any
Effects of CLCF1/CRLF1 deletion in mouse models
CLCF1 [37], CRLF1 [9] and CNTFR [38] null mice all die in the perinatal period due to a suckling defect, analogous to that observed in humans with CRLF1/CLCF1 mutations [27], [30]. No other gross defects have been noted, largely due to the early lethality of the phenotype. The suckling defect is associated with a significant reduction in the number of facial motor neurons [11]. Other factors may also contribute, such as atrophy of the facial muscles, and a defect in palate development, but
Effects of CLCF1 and CRLF1 composite cytokines on the neural system and neurodegeneration
Early studies of CLCF1 composite cytokines were quick to note their ability to support motor and sympathetic neuron survival [2], [6], [11] and to promote astrocyte differentiation [40]. It is likely for this reason that early studies to define the cause of the suckling defect in null mice focused on a deficiency in facial motor neuron survival [11]. In adults, CLCF1 is also expressed in the suprachiasmatic nucleus, where it colocalizes with clock genes and shows a circadian pattern of
Effects of CLCF1/CRLF1 composite cytokines on the musculoskeletal system
CLCF1 and CRLF1 are expressed within the developing murine skeleton, both in limb buds [9], [46] and in embryonic muscle and cartilage [11]. In a mouse model of ectopic bone formation, CRLF1 was detected by in situ hybridization in the cells that produce bone matrix (osteoblasts), and by the cells that constitute bone's internal neuron-like cellular network (osteocytes [47]) [48]. Although in situ detection has not been carried out in adult tissue, CLCF1, CRLF1 and CNTFR (but not NP) mRNAs are
Effects of CLCF1/CRLF1 composite cytokines in kidney development and disease
CLCF1 was detected in adult kidney when first described [2], and CRLF1 has recently been detected in developing kidneys [58]. CLCF1/CRLF1 not only induces STAT3 phosphorylation, but also promotes nephrogenesis in vitro [58], suggesting a role that promotes kidney development. However, since CLCF1 was barely detected in developing kidneys, it was suggested that this developmental action of CRLF1 might be mediated by an alternative ligand.
In adults, it has been suggested that CRLF1 may be a
Effects of CLCF1/CRLF1 composite cytokines on haematopoiesis and immune cell function
CLCF1 mRNA is strongly expressed in immune cells of adults [2], [3], [60]. CRLF1 is expressed in sites of haematopoiesis and immune cell maturation: adult spleen, thymus, and lymph node [46]. Transgenic overexpression of CLCF1 showed its ability to stimulate B cell differentiation and antibody production, including auto-antibodies [60]. However, since B cells do not express CNTFR, this suggested that CLCF1 acts on these cells through an alternate receptor complex [13].
CRLF1 expression is
Effects of CLCF1/CRLF1 composite cytokines on lung function, fibrosis and cancer
CLCF1 and CRLF1 were detected in the lung of developing mice [9], [46]. Although lung function in development was not assessed in the null mouse models, the respiratory distress suffered by patients with Crisponi/CSS1 syndrome is supportive of an essential role for these cytokines in lung development. In adulthood, CRLF1 expression was shown to be highly upregulated in idiopathic pulmonary fibrosis compared to normal controls [64]. Further work confirmed expression of CRLF1 and CNTFR in
Biological actions of NP
Neuropoietin was identified by an IL-6 structural profile-based computational genetic screen, and purified from embryonic mouse brain [4]. NP shares functional features with CNTF, CT-1, CLCF1, at least in terms of its ability to promote survival of embryonic motor neurons, neural precursor proliferation [4] and astrocyte differentiation [67] in vitro. NP colocalizes with CNTFR in the developing nervous system in murine embryonic neuroepithelia, retina and skeletal muscle, suggesting an
Concluding statements
There is still much to be learned about the roles of CLCF1/CRLF1 cytokines in biological function and the potential therapeutic applications of these cytokines and NP. In the last 10 years it has become clear that they are not merely developmental regulators of motor neuron function. The advent of microarray studies in a range of conditions has shown that upregulation of these poorly understood cytokines occurs in adult pathologies of the neural, musculoskeletal, respiratory, immune,
Natalie A. Sims directs the Bone Cell Biology and Disease Unit at St. Vincent's Institute and is a Principal Research Fellow and Associate Professor at The University of Melbourne. She completed her Ph.D. in 1995 at the University of Adelaide, and carried out postdoctoral studies at the Garvan Institute (Sydney) and Yale University, USA. Her main interest is in skeletal biology. She defined the roles of Oncostatin M, Cardiotrophin 1, and Leukaemia Inhibitory Factor on the development and
References (68)
- et al.
Computational EST database analysis identifies a novel member of the neuropoietic cytokine family
Biochem. Biophys. Res. Commun.
(1999) - et al.
Ciliary neurotrophic factor, cardiotrophin-like cytokine, and neuropoietin share a conserved binding site on the ciliary neurotrophic factor receptor α chain
J. Biol. Chem.
(2008) - et al.
Signaling pathways recruited by the cardiotrophin-like cytokine/cytokine-like factor-1 composite cytokine: specific requirement of the membrane-bound form of ciliary neurotrophic factor receptor alpha component
J. Biol. Chem.
(2001) - et al.
Two different contact sites are recruited by cardiotrophin-like cytokine (CLC) to generate the CLC/CLF and CLC/sCNTFRalpha composite cytokines
J. Biol. Chem.
(2004) - et al.
The ciliary neurotrophic factor and its receptor, CNTFR alpha
Pharm. Acta Helv.
(2000) - et al.
Cardiotrophin-like cytokine labelling using Bir A biotin ligase: a sensitive tool to study receptor expression by immune and non-immune cells
J. Immunol. Methods
(2005) - et al.
Neuropoietin activates STAT3 independent of LIFR activation in adipocytes
Biochem. Biophys. Res. Commun.
(2010) - et al.
regulates the synthesis and turnover of gp130, leukemia inhibitory factor receptor alpha, and oncostatin M receptor beta by distinct mechanisms
J. Biol. Chem.
(2001) - et al.
Stimulation of leukemia inhibitory factor receptor degradation by extracellular signal-regulated kinase
J. Biol. Chem.
(2000) - et al.
The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor
J. Biol. Chem.
(1998)
Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography
J. Biol. Chem.
Cold-induced sweating syndrome is caused by mutations in the CRLF1 gene
Am. J. Hum. Genet.
Cold-induced sweating syndrome: a report of two cases and demonstration of genetic heterogeneity
J. Neurol. Sci.
Crisponi syndrome is caused by mutations in the CRLF1 gene and is allelic to cold-induced sweating syndrome type 1
Am. J. Hum. Genet.
Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve–Wiedemann/Schwartz–Jampel type 2 syndrome
Am. J. Hum. Genet.
Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth
Cell
Cardiotrophin-like cytokine induces astrocyte differentiation of fetal neuroepithelial cells via activation of STAT3
Cytokine
Transcriptional profiling of the injured sciatic nerve of mice carrying the Wld(S) mutant gene: identification of genes involved in neuroprotection, neuroinflammation, and nerve regeneration
Brain Behav. Immun.
Quantifying the osteocyte network in the human skeleton
Bone
A gene expression profile for endochondral bone formation: oligonucleotide microarrays establish novel connections between known genes and BMP-2-induced bone formation in mouse quadriceps
Bone
Joint loading-driven bone formation and signaling pathways predicted from genome-wide expression profiles
Bone
Myokines (muscle-derived cytokines and chemokines) including ciliary neurotrophic factor (CNTF) inhibit osteoblast differentiation
Bone
Despite differential gene expression profiles pediatric MDS derived mesenchymal stromal cells display functionality in vitro
Stem Cell Res.
Cytokine-like factor 1 gene expression is enriched in idiopathic pulmonary fibrosis and drives the accumulation of CD4+ T cells in murine lungs: evidence for an antifibrotic role in bleomycin injury
Am. J. Pathol.
DJ-1 enhances cell survival through the binding of Cezanne, a negative regulator of NF-κB
J. Biol. Chem.
Neuropoietin induces neuroepithelial cells to differentiate into astrocytes via activation of STAT3
Cytokine
The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes
J. Biol. Chem.
CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex
Nat. Neurosci.
Novel neurotrophin-1/B cell-stimulating factor-3: a cytokine of the IL-6 family
Proc. Natl. Acad. Sci. U. S. A.
Neuropoietin, a new IL-6-related cytokine signaling through the ciliary neurotrophic factor receptor
Proc. Natl. Acad. Sci. U. S. A.
The ciliary neurotrophic factor receptor alpha component induces the secretion of and is required for functional responses to cardiotrophin-like cytokine
EMBO J.
Released form of CNTF receptor alpha component as a soluble mediator of CNTF responses
Science
Suckling defect in mice lacking the soluble haemopoietin receptor NR6
Curr. Biol.
Cardiotrophin-like cytokine/cytokine-like factor 1 is an essential trophic factor for lumbar and facial motoneurons in vivo
J. Neurosci.
Cited by (0)
Natalie A. Sims directs the Bone Cell Biology and Disease Unit at St. Vincent's Institute and is a Principal Research Fellow and Associate Professor at The University of Melbourne. She completed her Ph.D. in 1995 at the University of Adelaide, and carried out postdoctoral studies at the Garvan Institute (Sydney) and Yale University, USA. Her main interest is in skeletal biology. She defined the roles of Oncostatin M, Cardiotrophin 1, and Leukaemia Inhibitory Factor on the development and maintenance of the skeleton, using genetically altered mouse models and in vitro systems. Her current work continues to focus on paracrine control of the skeleton, particularly the way parathyroid hormone, IL-6 and STAT1/3 signalling influence bone formation and composition. Dr. Sims is a board member of the Australian and New Zealand Bone and Mineral Society, and the American Society for Bone and Mineral Research (ASBMR). She is a Senior Editor of the journal Bone, and Advisory Editor for Arthritis and Rheumatology.