Plun-Favreau H, Elson G, Chabbert M, Froger J, deLapeyrière O, Lelièvre E, Guillet C, Hermann J, Gauchat J F, Gascan H, Chevalier S
INSERM EMI 9928, CHU d'Angers, 4 Rue Larrey, 49033 Angers Cedex, France.
EMBO J. 2001 Apr 2;20(7):1692-703. doi: 10.1093/emboj/20.7.1692.
Ciliary neurotrophic factor (CNTF) is involved in the survival of a number of different neural cell types, including motor neurons. CNTF functional responses are mediated through a tripartite membrane receptor composed of two signalling receptor chains, gp130 and the leukaemia inhibitory factor receptor (LIFR), associated with a non-signalling CNTF binding receptor alpha component (CNTFR). CNTFR-deficient mice show profound neuronal deficits at birth, leading to a lethal phenotype. In contrast, inactivation of the CNTF gene leads only to a slight muscle weakness, mainly during adulthood, suggesting that CNTFR binds to a second ligand that is important for development. Modelling studies of the interleukin-6 family member cardiotrophin-like cytokine (CLC) revealed structural similarities with CNTF, including the conservation of a site I domain involved in binding to CNTFR. Co-expression of CLC and CNTFR in mammalian cells generates a secreted composite cytokine, displaying activities on cells expressing the gp130-LIFR complex on their surface. Correspondingly, CLC-CNTFR activates gp130, LIFR and STAT3 signalling components, and enhances motor neuron survival. Together, these observations demonstrate that CNTFR induces the secretion of CLC, as well as mediating the functional responses of CLC.
睫状神经营养因子（CNTF）参与多种不同神经细胞类型的存活，包括运动神经元。CNTF的功能反应是通过由两条信号受体链gp130和白血病抑制因子受体（LIFR）组成的三方膜受体介导的，该受体与非信号性CNTF结合受体α亚基（CNTFR）相关。缺乏CNTFR的小鼠在出生时表现出严重的神经元缺陷，导致致命的表型。相比之下，CNTF基因的失活仅导致轻微的肌肉无力，主要在成年期出现，这表明CNTFR与对发育重要的第二种配体结合。白细胞介素-6家族成员心肌营养素样细胞因子（CLC）的建模研究揭示了与CNTF的结构相似性，包括与CNTFR结合的位点I结构域的保守性。CLC和CNTFR在哺乳动物细胞中的共表达产生一种分泌的复合细胞因子，对表面表达gp130-LIFR复合物的细胞具有活性。相应地，CLC-CNTFR激活gp130、LIFR和STAT3信号成分，并增强运动神经元的存活。总之，这些观察结果表明CNTFR诱导CLC的分泌，并介导CLC的功能反应。
