Combined effects of GDNF, BDNF, and CNTF on motoneuron differentiation in vitro.
We have previously shown that glial cell line-derived neurotrophic factor (GDNF), in addition to promoting the survival of dopaminergic neurons in cultures from embryonic rat ventral mesencephalon,also increases the activity of choline acetyltransferase (ChAT) in the cranial motoneurons present in these cultures (Zurn et al.: Neuroreport 6:113-118, 1994). By using the intermediate filament protein peripherin as a motoneuron marker, we report here that GDNF increases the number of motoneurons as well as the length of their neurites. Brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) also promote ChAT activity, motoneuron survival, and neurite outgrowth in these cultures, but to varying degrees. Although these three molecules have similar effects on cultured motoneurons, we provide evidence for a distinct mode of action of GDNF, BDNF, and CNTF, since combinations of GDNF and BDNF, GDNF and CNTF, and BDNF and CNTF have either additive or synergistic 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 an important tool for the treatment of human motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy, both by increasing efficiency of treatment, and by decreasing the likelihood of deleterious side-effects.
Zurn
A D
AD
Gene Therapy Center, Lausanne University Medical School, Switzerland.
Winkel
L
L
Menoud
A
A
Djabali
K
K
Aebischer
P
P
D000818:Animals; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D020934:Ciliary Neurotrophic Factor; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005136:Eye Proteins / Q000032:analysis / Q000096:biosynthesis; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D007381:Intermediate Filament Proteins / Q000032:analysis / Q000096:biosynthesis; D008562:Membrane Glycoproteins; D008636:Mesencephalon / Q000166:cytology; D016472:Motor Neuron Disease; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009479:Neuropeptides / Q000032:analysis / Q000096:biosynthesis; D064531:Peripherins; D010751:Phosphopyruvate Hydratase / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology
D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D020934:Ciliary Neurotrophic Factor; D005136:Eye Proteins; C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C578994:PRPH protein, human; D064531:Peripherins; D011994:Recombinant Proteins; D002795:Choline O-Acetyltransferase; D010751:Phosphopyruvate Hydratase