Reelin induces EphB activation

TY - JOUR

T1 - Reelin induces EphB activation

AU - Bouché, Elisabeth

AU - Romero-Ortega, Mario I

AU - Henkemeyer, Mark

AU - Catchpole, Timothy

AU - Leemhuis, Jost

AU - Frotscher, Michael

AU - May, Petra

AU - Herz, Joachim

AU - Bock, Hans H

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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 differentiation events is the secreted glycoprotein Reelin, which also modulates synaptic plasticity, learning and memory formation 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 Disabled-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 repulsion-dependent processes via bidirectional signaling through ephrin B transmembrane proteins. Here, we demonstrate 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.

AB - 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 differentiation events is the secreted glycoprotein Reelin, which also modulates synaptic plasticity, learning and memory formation 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 Disabled-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 repulsion-dependent processes via bidirectional signaling through ephrin B transmembrane proteins. Here, we demonstrate 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.

KW - Animals

KW - Binding Sites

KW - COS Cells

KW - Cell Adhesion Molecules, Neuronal

KW - Cercopithecus aethiops

KW - Cerebral Cortex

KW - Embryo, Mammalian

KW - Extracellular Matrix Proteins

KW - Gene Expression Regulation, Developmental

KW - LDL-Receptor Related Proteins

KW - Mice

KW - Mice, Knockout

KW - Nerve Tissue Proteins

KW - Neuronal Plasticity

KW - Neurons

KW - Phosphorylation

KW - Protein Binding

KW - Protein Structure, Tertiary

KW - Receptor, EphB1

KW - Receptor, EphB2

KW - Receptors, LDL

KW - Serine Endopeptidases

KW - Signal Transduction

U2 - 10.1038/cr.2013.7

DO - 10.1038/cr.2013.7

M3 - SCORING: Journal article

C2 - 23318582

VL - 23

SP - 473

EP - 490

JO - CELL RES

JF - CELL RES

SN - 1001-0602

IS - 4

ER -