Cytoplasmic polyadenylation element-binding protein regulates neurotrophin-3-dependent beta-catenin mRNA translation in developing hippocampal neurons.
Neuronal morphogenesis, the growth and arborization of neuronal processes, is an essential component of brain development. Two important but seemingly disparate components regulating neuronal morphology have previously been described. In the hippocampus, neurotrophins, particularly brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3), act to enhance cell growth and branching, while activity-induced branching was shown to be dependent upon intracellular beta-catenin. We now describe a molecular link between NT3 stimulation and beta-catenin increase in developing neurons and demonstrate that this process is required for the NT3-mediated increase in process branching. Here, we show that beta-catenin is rapidly increased specifically in growth cones following NT3 stimulation. This increase in beta-catenin is protein synthesis dependent and requires the activity of cytoplasmic polyadenylation element-binding protein-1 (CPEB1), an mRNA-binding protein that regulates mRNA translation. We find that CPEB1 protein binds beta-catenin mRNA in a CPE-dependent manner and that both localize to growth cones of developing hippocampal neurons. Both the NT3-mediated rapid increase in beta-catenin and process branching are abolished when CPEB1 function is inhibited. In addition, the NT3-mediated increase in beta-catenin in growth cones is dependent upon internal calcium and the activity of CaMKII (calcium/calmodulin-dependent kinase II). Together, these results suggest that CPEB1 regulates beta-catenin synthesis in neurons and may contribute to neuronal morphogenesis.
Kundel
Mitchell
M
Department of Cell Biology, Yale University, New Haven, Connecticut 06520-8103, USA.
Jones
Kendrick J
KJ
Shin
Chan Y
CY
Wells
David G
DG
D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D020439:Growth Cones / Q000502:physiology; D006624:Hippocampus / Q000254:growth & development* / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D020933:Neurotrophin 3 / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
C539243:CPEB1 protein, rat; C495268:Ctnnb1 protein, rat; D020933:Neurotrophin 3; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051176:beta Catenin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium