Cardiotrophin-1, a Muscle-Derived Cytokine, Is Required for the Survival of Subpopulations of Developing Motoneurons

• Published in: The Journal of neuroscience 2001-02, Vol.21 (4), p.1283-1291
• Main Authors: Oppenheim, Ronald W, Wiese, Stefan, Prevette, David, Armanini, Mark, Wang, Siwei, Houenou, Lucien J, Holtmann, Bettina, Gotz, Rudolf, Pennica, Diane, Sendtner, Michael
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Axotomy; Brain Stem - embryology; Brain Stem - metabolism; Brain Stem - pathology; cardiotrophin-1; Cell Death; Cell Survival - drug effects; Cell Survival - genetics; Cells, Cultured; Chick Embryo; Ciliary Neurotrophic Factor - genetics; Ciliary Neurotrophic Factor - metabolism; Cytokine Receptor gp130; Cytokines - deficiency; Cytokines - genetics; Cytokines - metabolism; Cytokines - pharmacology; Dose-Response Relationship, Drug; Facial Nerve; Growth Inhibitors - genetics; Growth Inhibitors - metabolism; Interleukin-6; Leukemia Inhibitory Factor; Lymphokines - genetics; Lymphokines - metabolism; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Knockout; Motor Neurons - drug effects; Motor Neurons - metabolism; Motor Neurons - pathology; Muscle, Skeletal - embryology; Muscle, Skeletal - innervation; Muscle, Skeletal - metabolism; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Receptor, Ciliary Neurotrophic Factor - genetics; Receptor, Ciliary Neurotrophic Factor - metabolism; RNA, Messenger - biosynthesis; Spinal Cord - embryology; Spinal Cord - metabolism; Spinal Cord - pathology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.21-04-01283.2001

Developing motoneurons require trophic support from their target, the skeletal muscle. Despite a large number of neurotrophic molecules with survival-promoting activity for isolated embryonic motoneurons, those factors that are required for motoneuron survival during development are still not known. Cytokines of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory factor (LIF) family have been shown to play a role in motoneuron (MN) survival. Importantly, in mice lacking the LIFRbeta or the CNTFRalpha there is a significant loss of MNs during embryonic development. Because genetic deletion of either (or both) CNTF or LIF fails, by contrast, to perturb MN survival before birth, it was concluded that another ligand exists that is functionally inactivated in the receptor deleted mice, resulting in MN loss during development. One possible candidate for this ligand is the CNTF-LIF family member cardiotrophin-1 (CT-1). CT-1 is highly expressed in embryonic skeletal muscle, secreted by myotubes, and promotes the survival of cultured embryonic mouse and rat MNs. Here we show that ct-1 deficiency causes increased motoneuron cell death in spinal cord and brainstem nuclei of mice during a period between embryonic day 14 and the first postnatal week. Interestingly, no further loss was detectable during the subsequent postnatal period, and nerve lesion in young adult ct-1-deficient mice did not result in significant additional loss of motoneurons, as had been previously observed in mice lacking both CNTF and LIF. CT-1 is the first bona fide muscle-derived neurotrophic factor to be identified that is required for the survival of subgroups of developing motoneurons.