Reelin induces EphB activation

被引:57
作者
Bouche, Elisabeth [1 ,2 ]
Romero-Ortega, Mario I. [3 ]
Henkemeyer, Mark [4 ]
Catchpole, Timothy [4 ]
Leemhuis, Jost [1 ]
Frotscher, Michael [1 ,5 ]
May, Petra [1 ,2 ,6 ]
Herz, Joachim [1 ,7 ]
Bock, Hans H. [1 ,2 ,6 ]
机构
[1] Univ Freiburg, Ctr Neurosci, D-79104 Freiburg, Germany
[2] Univ Freiburg, Dept Med 2, D-79104 Freiburg, Germany
[3] Univ Texas Arlington, Dept Biomed Engn, Arlington, TX 76019 USA
[4] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA
[5] Ctr Mol Neurobiol, Hamburg, Germany
[6] Univ Dusseldorf, Clin Gastroenterol Hepatol & Infectiol, D-40225 Dusseldorf, Germany
[7] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA
关键词
signal transduction; signaling crosstalk; tyrosine kinase; ephrin; lipoprotein receptor; hippocampus; neural development; CENTRAL-NERVOUS-SYSTEM; APOE RECEPTOR 2; NEURONAL MIGRATION; BRAIN-DEVELOPMENT; LIPOPROTEIN RECEPTORS; SYNAPTIC PLASTICITY; TYROSINE PHOSPHORYLATION; CELL-PROLIFERATION; NEURAL DEVELOPMENT; GAMMA-SECRETASE;
D O I
10.1038/cr.2013.7
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
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 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.
引用
收藏
页码:473 / 490
页数:18
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