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The Journal of Neuroscience, February 15, 2001, 21(4):1283-1291

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

Ronald W. Oppenheim¹, Stefan Wiese⁴, David Prevette¹, Mark Armanini², Siwei Wang¹, Lucien J. Houenou¹, Bettina Holtmann⁴, Rudolf Götz⁴, Diane Pennica³, and Michael Sendtner⁴

¹ Department of Neurobiology and Anatomy and the Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, Departments of ² Cell Biology and Technology and ³ Molecular Oncology, Genentech, South San Francisco, California 94080, and ⁴ Klinische Forschergruppe Neuroregeneration, Department of Neurology, University of Wuerzburg, 97080 Wuerzburg, Germany

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 LIFR or the CNTFR 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.

Key words: programmed cell death; spinal cord; CNTF; LIF; facial motoneurons; axotomy

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2141283-09$05.00/0

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