CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex

Ciliary neurotrophic factor (CNTF) is a cytokine supporting the differentia tion and survival of various cell types in the peripheral and central nervo us systems. Its receptor complex consists of a non-signaling alpha chain, C NTFR, and two signaling beta chains, gp130 and the leukemia inhibitory fact or receptor (LIFR). Striking phenotypic differences between CNTF- and CNTFR -deficient mice suggest that CNTFR serves as a receptor for a second, devel opmentally important ligand. We have identified this factor as a stable sec reted complex of cardiotrophin-like cytokine (CLC) and the soluble receptor cytokine-like factor-1 (CLF). CLF expression was required for CLC secretio n, and the complex acted only on cells expressing functional CNTF receptors . The CLF/CLC complex activated gp130, LIFR and signal transducer and activ ator of transcription 3 (STAT3) and supported motor neuron survival. Our re sults indicate that the CLF/CLC complex is a second ligand for CNTFR with p otentially important implications in nervous system development.