COMBINED EFFECTS OF GDNF, BDNF, AND CNTF ON MOTONEURON DIFFERENTIATION IN-VITRO

We have previously shown that glial cell line-derived neurotrophic fac tor (GDNF), in addition to promoting the survival of dopaminergic neur ons in cultures from embryonic rat ventral mesencephalon, also increas es the activity of choline acetyltransferase (ChAT) in the cranial mot oneurons present in these cultures (Zurn et al.: Neuroreport 6:113-118 , 1994). By using the intermediate filament protein peripherin as a mo toneuron marker, we report here that GDNF increases the number of moto neurons as well as the length of their neurites. Brain-derived neurotr ophic factor (BDNF) and ciliary neurotrophic factor (CNTF) also promot e ChAT activity, motoneuron survival, and neurite outgrowth in these c ultures, but to varying degrees. Although these three molecules have s imilar effects on cultured motoneurons, we provide evidence for a dist inct mode of action of GDNF, BDNF, and CNTF, since combinations of GDN F and BDNF, GDNF and CNTF, and BDNF and CNTF have either additive or s ynergistic effects on ChAT activity and motoneuron number. In addition to the previously described motoneuron-specific neurotrophic factors BDNF and CNTF, GDNF combined with the latter two factors may provide a n important tool for the treatment of human motoneuron diseases such a s amyotrophic lateral sclerosis and spinal muscular atrophy, both by i ncreasing efficiency of treatment, and by decreasing the likelihood of deleterious side-effects. (C) 1996 Wiley-Liss, Inc.