Reelin induces EphB activation  

作　　者：Elisabeth Bouche Mario I Romero-Ortega Mark Henkemeyer Timothy Catchpole Jost Leemhuis Michael Frotscher Petra May Joachim Herz Hans H Bock 

机构地区：[1]Center for Neuroscience, Albert-Ludwigs-University, Albertstrasse 23, D-79104 Freiburg, Germany [2]Department of Medicine II, Albert-Ludwigs-University, Freiburg, Germany [3]Department of Biomedical Engineering, University of Texas at Arlington,Arlington, TX 76019, USA [4]Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA [5]Center for Molecular Neurobiology, Hamburg, Germany [6]Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University Diisseldorf Moorenstrasse 5, D-40225 Diisseldorf Germany [7]Department of Molecular Genetics,University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

出　　处：《Cell Research》2013年第4期473-490,共18页细胞研究（英文版）

摘　　要：The integration of newborn neurons into functional neuronal networks requires migration of cells to their final position in the developing brain, the growth and arborization of neuronal processes and the formation of synaptic contacts with other neurons. A central player among the signals that coordinate this complex sequence of differentia- tion events is the secreted glycoprotein Reelin, which also modulates synaptic plasticity, learning and memory forma- tion in the adult brain. Binding of Reelin to ApoER2 and VLDL receptor, two members of the LDL receptor family, initiates a signaling cascade involving tyrosine phosphorylation of the intracellular cytoplasmic adaptor protein Dis- abled-1, which targets the neuronal cytoskeleton and ultimately controls the positioning of neurons throughout the developing brain. However, it is possible that Reelin signals interact with other receptor-mediated signaling cascades to regulate different aspects of brain development and plasticity. EphB tyrosine kinases regulate cell adhesion and re- pulsion-dependent processes via bidirectional signaling through ephrin B transmembrane proteins. Here, we demon- strate that Reelin binds to the extracellular domains of EphB transmembrane proteins, inducing receptor clustering and activation of EphB forward signaling in neurons, independently of the ＇classical＇ Reelin receptors, ApoER2 and VLDLR. Accordingly, mice lacking EphB1 and EphB2 display a positioning defect of CA3 hippocampal pyramidal neurons, similar to that in Reelin-deficient mice, and this cell migration defect depends on the kinase activity of EphB proteins. Together, our data provide biochemical and functional evidence for signal integration between Reelin and EphB forward signaling.The integration of newborn neurons into functional neuronal networks requires migration of cells to their final position in the developing brain, the growth and arborization of neuronal processes and the formation of synaptic contacts with other neurons. A central player among the signals that coordinate this complex sequence of differentia- tion events is the secreted glycoprotein Reelin, which also modulates synaptic plasticity, learning and memory forma- tion in the adult brain. Binding of Reelin to ApoER2 and VLDL receptor, two members of the LDL receptor family, initiates a signaling cascade involving tyrosine phosphorylation of the intracellular cytoplasmic adaptor protein Dis- abled-1, which targets the neuronal cytoskeleton and ultimately controls the positioning of neurons throughout the developing brain. However, it is possible that Reelin signals interact with other receptor-mediated signaling cascades to regulate different aspects of brain development and plasticity. EphB tyrosine kinases regulate cell adhesion and re- pulsion-dependent processes via bidirectional signaling through ephrin B transmembrane proteins. Here, we demon- strate that Reelin binds to the extracellular domains of EphB transmembrane proteins, inducing receptor clustering and activation of EphB forward signaling in neurons, independently of the ＇classical＇ Reelin receptors, ApoER2 and VLDLR. Accordingly, mice lacking EphB1 and EphB2 display a positioning defect of CA3 hippocampal pyramidal neurons, similar to that in Reelin-deficient mice, and this cell migration defect depends on the kinase activity of EphB proteins. Together, our data provide biochemical and functional evidence for signal integration between Reelin and EphB forward signaling.

关 键 词：signal transduction signaling crosstalk tyrosine kinase EPHRIN lipoprotein receptor HIPPOCAMPUS neural development 

分 类 号：Q513.5[生物学—生物化学] Q26