Current Biology
Volume 6, Issue 6, June 1996, Pages 686-694
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Research Paper
Cryptic physiological trophic support of motoneurons by LIF revealed by double gene targeting of CNTF and LIF

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Abstract

Background The survival and differentiation of motoneurons during embryonic development, and the maintenance of their function in the postnatal phase, are regulated by a great variety of neurotrophic molecules which mediate their effects through different receptor systems. The multifactorial support of motoneurons represents a system of high security, because the inactivation of individual ligands has either no detectable, or relatively small, atrophic or degenerative effect on motoneurons.

Results Leukaemia inhibitory factor (LIF) has been demonstrated to support motoneuron survival in vitro and in vivo under different experimental conditions. However, when LIF was inactivated by gene targeting, there were no apparent changes in the number and structure of motoneurons and no impairment of their function. The slowly appearing, relatively mild degenerating effects in motoneurons that resulted from ciliary neurotrophic factor (CNTF) gene targeting were substantially potentiated by simultaneous inactivation of the LIF gene, however. Thus, in mice deficient in LIF and CNTF, the degenerative changes in motoneurons were more extensive and appeared earlier. These changes were also functionally reflected by a marked reduction in grip strength.

Conclusion Degenerative disorders of the nervous system, in particular those of motoneurons, may be based on multifactorial inherited and/or acquired defects which individually do not result in degenerative disorders, but which become apparent when additional (cryptic) inherited disturbances or sub-threshold concentrations of noxious factors come into play. Accordingly, the inherited inactivation of the CNTF gene in a high proportion of the Japanese population may represent a predisposing factor for degenerative disorders of motoneurons.

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M. Sendtner, R. Götz, B. Holtmann, Department of Neurology, University of Würzburg, Josef-Schneider Str. 11, 97080 Würzburg, Germany, and Department of Neurochemistry, Max-Planck-Institute for Psychiatry, Am Klopferspitz 18a, 82152 Martinsried, Germany.

Y. Masu, P. Carroll and H. Thoenen (corresponding author), Department of Neurochemistry, Max-Planck-Institute for Psychiatry, Am Klopferspitz 18a, 82152 Martinsried, Germany.

J-L. Escary and P. Brûlet, Unité d’ Embryologie Moléculaire de l’Institut Pasteur, URA 1148 du CNRS, 75724 Paris Cedex 15, France.

E. Wolf and G. Brem, Abteilung für Molekulare Tierzucht, Ludwig-Maximilians-Universität München, 80539 München, Germany.