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The Journal of Neuroscience, October 1, 2003, 23(26):8854-8858

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BRIEF COMMUNICATION
Cardiotrophin-Like Cytokine/Cytokine-Like Factor 1 is an Essential Trophic Factor for Lumbar and Facial Motoneurons In Vivo

Nancy G. Forger,¹ David Prevette,² Odile deLapeyrière,³ Béatrice de Bovis,³ Siwei Wang,² Perry Bartlett,⁴ and Ronald W. Oppenheim²

¹Department of Psychology and Center for Neuroendocrine Studies, University of Massachusetts, Amherst, Massachusetts 01003, ²Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, ³Institut National de la Santé et de la Recherche Médicale (INSERM) U.382, Developmental Biology Institute of Marseille, Centre National de la Recherche Scientifique-INSERM-Universite de la Mediterranee, 13288 Marseille Cedex 09, France, and ⁴School of Biomedical Sciences, University of Queensland, Brisbane 4067 Australia

The ciliary neurotrophic factor -receptor (CNTFR) is required for motoneuron survival during development, but the relevant ligand(s) has not been determined. One candidate is the heterodimer formed by cardiotrophin-like cytokine (CLC) and cytokine-like factor 1 (CLF). CLC/CLF binds to CNTFR and enhances the survival of developing motoneurons in vitro; whether this novel trophic factor plays a role in neural development in vivo has not been tested. We examined motor and sensory neurons in embryonic chicks treated with CLC and in mice with a targeted deletion of the clf gene. Treatment with CLC increased the number of lumbar spinal cord motoneurons that survived the cell death period in chicks. However, this effect was regionally specific, because brachial and thoracic motoneurons were unaffected. Similarly, newborn clf-/- mice exhibited a significant reduction in lumbar motoneurons, with no change in the brachial or thoracic cord. Clf deletion also affected brainstem motor nuclei in a regionally specific manner; the number of motoneurons in the facial but not hypoglossal nucleus was significantly reduced. Sensory neurons of the dorsal root ganglia were not affected by either CLC treatment or clf gene deletion. Finally, mRNA for both clc and clf was found in skeletal muscle fibers of embryonic mice during the motoneuron cell death period. These findings support the view that CLC/CLF is a target-derived factor required for the survival of specific pools of motoneurons. The in vivo actions of CLC and CLF can account for many of the effects of CNTFR on developing motoneurons.

Key words: motoneuron; cell death; trophic factor; cardiotrophin; cytokine; ciliary neurotrophic factor

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Received June 5, 2003; revised August 1, 2003; accepted August 4, 2003.

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