Rw. Oppenheim et al., Cardiotrophin-1, a muscle-derived cytokine, is required for the survival of subpopulations of developing motoneurons, J NEUROSC, 21(4), 2001, pp. 1283-1291
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.