Interactions between beta-neuregulin and neurotrophins in motor neuron apoptosis.
Neuregulins play a major role in the formation and stabilization of neuromuscular junctions, and are produced by both motor neurons and muscle. Although the effects and mechanism of neuregulins on skeletal muscle (e.g. regulation of acetylcholine receptor expression) have been studied extensively, the effects of neuregulins on motor neurons remain unknown. We report that neuregulin-1beta (NRGbeta1) inhibited apoptosis of rat motor neurons for up to 7 days in culture by a phosphatidylinositol 3 kinase-dependent pathway and synergistically enhanced motor neuron survival promoted by glial-derived neurotrophic factor (GDNF). However, binding of neurotrophins, including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), to the p75 neurotrophin receptor (p75NTR) abolished the neuregulin anti-apoptotic effect on motor neurons. Inhibitors of the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase prevented motor neuron death caused by co-incubation of NRGbeta1 and BDNF or NGF, as well as by trophic factor deprivation. Motor neuron apoptosis resulting from both trophic factor deprivation and exposure to NRGbeta1 plus neurotrophins required the induction of neuronal nitric oxide synthase and peroxynitrite formation. Because motor neurons express both p75NTR and neuregulin erbB receptors during the period of embryonic programmed cell death, motor neuron survival may be the result of complex interactions between trophic and death factors, which may be the same molecules acting in different combinations.
Ricart
Karina
K
Department of Physiology and Biophysics, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
J Pearson
Richard
R
Viera
Liliana
L
Cassina
Patricia
P
Kamaid
Andrés
A
Carroll
Steven L
SL
Estévez
Alvaro G
AG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000819:agonists / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D020890:Neuregulin-1 / Q000378:metabolism* / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000187:drug effects / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000819:agonists / Q000378:metabolism; D013116:Spinal Cord / Q000196:embryology* / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D020890:Neuregulin-1; D020800:Receptor, Nerve Growth Factor; C117467:neuregulin beta; D030421:Peroxynitrous Acid; D020932:Nerve Growth Factor; D052248:Nitric Oxide Synthase Type I; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases