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. 2003 Oct 1;23(26):8854-8.
doi: 10.1523/JNEUROSCI.23-26-08854.2003.

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, Odile deLapeyrière, Béatrice de Bovis, Siwei Wang, Perry Bartlett, Ronald W Oppenheim
Affiliations

Cardiotrophin-like cytokine/cytokine-like factor 1 is an essential trophic factor for lumbar and facial motoneurons in vivo

Nancy G Forger et al. J Neurosci. .

Abstract

The ciliary neurotrophic factor alpha-receptor (CNTFRalpha) 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 CNTFRalpha 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 CNTFRalpha on developing motoneurons.

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Figures

Figure 1.
Figure 1.
Effect of CLC, CT-1, and CNTF alone and in combination on the survival of embryonic chick motoneurons in culture. Data are expressed as a percentage of survival (mean ± SEM) relative to chick embryo MEX. Data from four independent replications were analyzed by ANOVA followed by planned comparisons. *, Significantly different from control condition; †, significantly different from CLC alone.
Figure 2.
Figure 2.
Detection of clc (A) and clf (B) mRNAs (blue staining) in transverse sections of E16.5 mouse embryos at the lumbar level by in situ hybridization. Muscle tissue is positive for both probes (arrows). Also note clf expression in the kidney as described by Alexander et al. (1999). The identity of the clc- or clf-positive cells as muscle fibers was confirmed by double staining. In situ hybridization using DIG-labeled probes for clc (C) and clf (D) was performed on sections of thigh muscles from E16.5 MLCnlacZ mice, which express the nlacZ reporter gene under the control of a muscle-specific MLC promoter. Subsequently, the sections were processed for immunohistochemical detection of β-Gal. Strongly clc- or clf-positive cells (blue cytoplasmic staining) are also β-Gal positive (brown nuclear staining). Arrows indicate double-labeled cells. sc, Spinal cord; k, kidney; c, cartilage.
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