Mini review
Cardiotrophin-like cytokine factor 1 (CLCF1) and neuropoietin (NP) signalling and their roles in development, adulthood, cancer and degenerative disorders

https://doi.org/10.1016/j.cytogfr.2015.07.014Get rights and content

Highlights

  • Signalling complexes formed by CLCF1, CRLF1 and neuropoietin are described.

  • The roles of CLCF1 and CRLF1 in human and murine development are described.

  • CLCF1 and CRLF1 affect kidney and lung pathology, osteoarthritis and haematopoiesis.

  • Potential results of targeting these pathways in human pathology are suggested.

Abstract

Mutations in cardiotrophin-like cytokine factor (CLCF1) and the related cytokine to which it binds, cytokine receptor-like factor 1 (CRLF1), are associated with Crisponi/cold induced sweating syndromes, and lead to early neonatal death in mice due to a suckling defect. These cytokines are members of the IL-6 superfamily, and form a range of composite cytokines that signal through gp130 bound either to the ciliary neurotrophic factor receptor (CNTFR) or a complex that involves the IL-27 p28 subunit. This review describes current knowledge of the signalling complexes formed by these cytokines, and explores their described and suggested roles in the neural, haematopoietic, skeletal, renal, immune and respiratory systems during development and adulthood, and in degenerative diseases and cancer.

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

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    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.

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