Cardiotrophin-1, a muscle-derived cytokine, is required for the survival of subpopulations of developing motoneurons

Developing motoneurons require trophic support from their target, the skele tal muscle. Despite a large number of neurotrophic molecules with survival- promoting activity for isolated embryonic motoneurons, those factors that a re required for motoneuron survival during development are still not known. Cytokines of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory fa ctor (LIF) family have been shown to play a role in motoneuron (MN) surviva l. Importantly, in mice lacking the LIFR beta or the CNTFR alpha there is a significant loss of MNs during embryonic development. Because genetic dele tion of either (or both) CNTF or LIF fails, by contrast, to perturb MN surv ival before birth, it was concluded that another ligand exists that is func tionally inactivated in the receptor deleted mice, resulting in MN loss dur ing development. One possible candidate for this ligand is the CNTF-LIF fam ily member cardiotrophin-1 (CT-1). CT-1 is highly expressed in embryonic sk eletal muscle, secreted by myotubes, and promotes the survival of cultured embryonic mouse and rat MNs. Here we show that ct-1 deficiency causes incre ased motoneuron cell death in spinal cord and brainstem nuclei of mice duri ng a period between embryonic day 14 and the first postnatal week. Interest ingly, no further loss was detectable during the subsequent postnatal perio d, and nerve lesion in young adult ct-1-deficient mice did not result in si gnificant additional loss of motoneurons, as had been previously observed i n mice lacking both CNTF and LIF. CT-1 is the first bona fide muscle-derive d neurotrophic factor to be identified that is required for the survival of subgroups of developing motoneurons.