The role of p75NTR in modulating neurotrophin survival effects in developing motoneurons.
Neurotrophins exert their biological functions on neuronal cells through two types of receptors, the trk tyrosine kinases and the low-affinity neurotrophin receptor (p75NTR), which can bind all neurotrophins with similar affinity. The p75NTR is highly expressed in developing motoneurons and in adult motoneurons after axotomy, suggestive of a physiological role in mediating neurotrophin responses under such conditions. In order to characterize this specific function of p75NTR, we have tested the effects of nerve growth factor (NGF) on embryonic motoneurons from control and p75NTR-deficient mice. NGF antagonizes brain-derived neurotrophic factor (BDNF)- and neurotrophin-3 (NT-3)-mediated survival in control but not p75NTR-deficient motoneurons. Survival of cultured motoneurons in the presence of 0.5 ng/mL of either ciliary neurotrophic factor (CNTF) or glial-derived neurotrophic factor (GDNF) was not reduced by 20 ng/mL NGF. Dose-response investigations revealed that five times higher concentrations of BDNF are required for half-maximal survival of p75NTR-deficient motoneurons in comparison to motoneurons from wild-type controls. After facial nerve lesion in newborn wild-type mice, local administration of NGF reduced survival of corresponding motoneurons to less than 2% compared to the unlesioned control side. In p75NTR-deficient mice, the same treatment did not enhance facial motoneuron death on the lesioned side. In the facial nucleus of 1-week-old p75NTR -/- mice, a significant reduction of motoneurons was observed at the unlesioned side in comparison to p75NTR +/+ mice. The observation that motoneuron cell numbers are reduced in the facial nucleus of newborn p75NTR-deficient mice suggests that p75NTR might not function as a physiological cell death receptor in developing motoneurons.
Wiese
S
S
Klinische Forschergruppe Neuroregeneration, Department of Neurology, University of Würzburg, Germany.
Metzger
F
F
Holtmann
B
B
Sendtner
M
M
D000818:Animals; D000831:Animals, Newborn; D019771:Axotomy; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor; D004305:Dose-Response Relationship, Drug; D005154:Facial Nerve / Q000166:cytology / Q000601:surgery; D005333:Fetus / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D020933:Neurotrophin 3; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D020934:Ciliary Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor