A neuron-specific EGF family protein, NELL2, promotes survival of neurons through mitogen-activated protein kinases.
NELL2 is a neuron-specific thrombospondin-1-like extracellular protein containing six epidermal growth factor-like domains. NELL2 is highly expressed in the hippocampus and cerebral cortex. Although the involvement of NELL2 in neural functions has been inferred from its expression and biochemical profiles, biological roles of NELL2 remain uncertain. We evaluated the survival effect of NELL2 using primary cultured neurons from fetal rat brain following treatment with a recombinant NELL2 protein. NELL2 increased survival of neurons from the hippocampus and cerebral cortex. We further examined the protective effect of NELL2 from oxygen-glucose deprivation- and beta-amyloid-induced neuronal death, and found that NELL2 did not protect neurons from these insults. To understand signaling properties underlying the survival effect, we studied activation of mitogen-activated protein kinases (MAPKs) by NELL2. Treatment of primary cultured cells from the hippocampus with NELL2 enhanced phosphorylation of c-jun N-terminal kinase (JNK), whereas phosphorylation of extracellular signal-regulated kinase (ERK) was decreased by NELL2 treatment. NELL2-enhanced survival of hippocampal neurons was completely blocked by SP600125, an anthrapyrazolone inhibitor of JNK, while treatment of MEK (MAPK/ERK kinase) inhibitors per se enhanced survival of neurons similar to NELL2 treatment. These results suggest that NELL2 promotes survival of neurons by modulating MAPK activities.
Aihara
Koutoku
K
Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
Kuroda
Shun'ichi
S
Kanayama
Norihiro
N
Matsuyama
Shogo
S
Tanizawa
Katsuyuki
K
Horie
Masato
M
D016229:Amyloid beta-Peptides / Q000008:administration & dosage; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004815:Epidermal Growth Factor / Q000737:chemistry; D004958:Estradiol / Q000008:administration & dosage; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; C104145:NELL2 protein, human; C491252:Nell2 protein, rat; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D016222:Fibroblast Growth Factor 2; D004958:Estradiol; D004815:Epidermal Growth Factor; D016291:Dizocilpine Maleate; D048056:Mitogen-Activated Protein Kinase 9; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose; D010100:Oxygen