CRYPTIC PHYSIOLOGICAL TROPHIC SUPPORT OF MOTONEURONS BY LIF REVEALED BY DOUBLE GENE TARGETING OF CNTF AND LIF

Background: The survival and differentiation of motoneurons during emb ryonic development, and the maintenance of their function in the postn atal phase, are regulated by a great variety of neurotrophic molecules which mediate their effects through different receptor systems. The m ultifactorial support of motoneurons represents a system of high secur ity, because the inactivation of individual ligands has either no dete ctable, or relatively small, atrophic or degenerative effect on motone urons. Results: Leukaemia inhibitory factor (LIF) has been demonstrate d to support motoneuron survival in vitro and in vivo under different experimental conditions. However, when LIF was inactivated by gene tar geting, 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 fro m ciliary neurotrophic factor (CNTF) gene targeting were substantially potentiated by simultaneous inactivation of the LIF gene, however. Th us, in mice deficient in LIF and CNTF, the degenerative changes in mot oneurons were more extensive and appeared earlier. These changes were also functionally reflected by a marked reduction in grip strength. Co nclusions: 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 dis orders, but which become apparent when additional (cryptic) inherited disturbances or sub-threshold concentrations of noxious factors come i nto play. Accordingly, the inherited inactivation of the CNTF gene in a high proportion of the Japanese population may represent a predispos ing factor for degenerative disorders of motoneurons.