EphB2 Tyrosine Kinase-Dependent Forward Signaling in Migration of Neuronal Progenitors That Populate and Form a Distinct Region of the Dentate Niche

Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2011; 31(32):11472-83. DOI: 10.1523/JNEUROSCI.6349-10.2011
Source: PubMed


The dentate gyrus (DG) is one of two areas in the mature brain where stem cells reside to continuously produce new neurons throughout adulthood. While much research has focused on the DG for its roles in adult neurogenesis, little is known regarding how this key region of the brain initially develops to form its distinct architecture. We show here that the murine EphB2 receptor tyrosine kinase is critical for embryonic/postnatal development of a specific region of the DG known as the lateral suprapyramidal blade (LSB). Intracellular truncation and point mutants demonstrate that EphB2 catalytic activity is essential for LSB formation. This is consistent with expression of EphB2 in nestin-positive neural progenitor cells that migrate medially from the lateral ventricle dentate notch neuroepithelium to populate the tertiary matrix and form the DG near the midline of the brain. Animals lacking ephrin-B1 recapitulate loss of the receptor and show that this molecule acts as the ligand to stimulate EphB2 forward signaling and direct migration of the neural progenitors into the dorsal compartment of the tertiary matrix and form the LSB. Immunoreactivity against the extracellular matrix protein Reelin in a region directly above the developing LSB is dramatically reduced when EphB2 forward signaling is disrupted. Together, these results indicate ephrin-B1 interacting with EphB2 controls the migration of dentate progenitor cells into the dorsal half of the developing DG, perhaps in part by affecting Reelin expression in a key compartment directly above the LSB.

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    • ") (Kodosecitch et et. 2011 25 ) (Chumley et al. 2007 20 ) (Hara et al. 2010 26 ) Dentate Gyrus ephrin B1 (Catchpole et al. 2011 21 ) Astrocytes Eph A4 ephrin A2 ephrin A3 ephrin B2 (Jiao et al. 2008; 24 Ashton et al. 2012; 22 Kodosecitch et. 2011 25 ) Mature granule neurons ephrin A5 (Hara et al. 2010 26 ) 352 "
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    ABSTRACT: Eph:ephrin signaling plays an important role in embryonic development as well as tissue homeostasis in the adult. At the cellular level, this transduction pathway is best known for its role in the control of cell adhesion and repulsion, cell migration and morphogenesis. Yet, a number of publications have also implicated Eph:ephrin signaling in the control of adult and embryonic neurogenesis. As is the case for other biological processes, these studies have reported conflicting and sometimes opposite roles for Eph:ephrin signaling in neurogenesis. Herein, we review these studies and we discuss existing mathematical models of stem cell dynamics and neurogenesis that provide a coherent framework and may help reconcile conflicting results.
    Cell adhesion & migration 11/2014; 8:349-359. · 4.51 Impact Factor
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    • "Moreover, mice lacking only EphB2 display a circumscribed defect in the development of the lateral subregion of the suprapyramidal granule cell layer of the dentate gyrus. This phenotype is recapitulated in mice that do not express the ephrin B1 ligand37. However, compared with wild-type mice and single EphB mutants, histological evaluation of the medial cornu ammonis area 3 (CA3) in the hippocampus of Ephb1;Ephb2 compound null mice revealed abnormally broader localization, and thus abnormal migration of pyramidal neurons in this region but not in CA1 (boxed area, Figure 7A). "
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    ABSTRACT: 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.Cell Research advance online publication 15 January 2013; doi:10.1038/cr.2013.7.
    Cell Research 01/2013; 23(4). DOI:10.1038/cr.2013.7 · 12.41 Impact Factor
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    • "Differences in cell vulnerabilities exist; for instance, IL-2 deficiency results in a greater loss of infrapyramidal than suprapyramidal granule cell numbers (Beck et al.,2005), whereas the infrapyramidal blade shows a greater sensitivity to hypoxia (Hara et al., 1990). Mutation of Lmx1a in the Dreher mouse preferentially results in loss of the infrapyramidal blade (Sekiguchi et al.,1992), whereas mutation of EphB2 results in loss of just the lateral portion of the suprapyramidal blade (Catchpole and Henkemeyer,2011). Numbers of neurons can differ between the blades, for instance, in two strains of seizure-prone mice numbers of granule and basket cells were higher in the suprapyramidal than infrapyramidal blade (Wimer et al.,1990). "
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    ABSTRACT: The nuclear receptor ligand retinoic acid (RA) has been identified as an endogenous regulatory factor in the hippocampus, acting on pyramidal neurons and granule neuron progenitors, but almost nothing is known about the distribution of RA itself in the hippocampus. This study describes the source of RA for the rodent hippocampus in the meninges via the key RA synthetic enzyme retinaldehyde dehydrogenase 2 (RALDH2). Diffusion of RA from the meninges potentially creates a gradient of RA across the infrapyramidal and suprapyramidal blades of the dentate gyrus, enhanced by the expression of the RA catabolic enzyme Cyp26B1 between the blades, and an infrapyramidal and suprapyramidal blade difference is evident in RA-regulated transcription. This asymmetry may contribute to some of the physiological and molecular differences between the blades, including a disparity in the rates of cell proliferation in the subgranular zone of the two blades through RA inhibition of cell proliferation. Such differences can be altered by either the application of excess RA, its effect dependent on the relative position along the septotemporal axis, or change in RA signaling through mutation of retinol binding protein, while the capacity of RA to inhibit proliferation of cells in the dentate gyrus is demonstrated using in vitro slice culture. Use of synthetic and catabolic enzymes in the hippocampus to create differing zones of RA concentration parallels the mechanisms used in the developing brain to generate patterns of RA-regulated transcription. © 2012 Wiley Periodicals, Inc.
    Hippocampus 11/2012; 22(11):2171-83. DOI:10.1002/hipo.22037 · 4.16 Impact Factor
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