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.

  • Source
    • ") (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 "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Nov 2014 · Cell adhesion & migration
  • Source
    • "Eph receptors can generate kinase-dependent " forward " signals, in which ligand binding triggers receptor dimerization, activating the intrinsic kinase activity of the receptor, and initiating responses in the receptor-expressing cell. Kinase-dependent forward Eph signaling contributes to many processes including retinotopic mapping (Hindges et al. 2002), axonal midline avoidance after crossing (Yokoyama et al. 2001), neural crest cell migration (Smith et al. 1997), and migration of neural progenitors (Catchpole and Henkemeyer 2011). This regulation of diverse developmental processes occurs in part via kinase-dependent interactions with downstream effectors including Src-family kinases (Zisch et al. 1998; Knoll and Drescher 2004), Rho GTPases (Wahl et al. 2000; Noren and Pasquale 2004), and RhoGEFs (Shamah et al. 2001; Sahin et al. 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Eph receptors and their ephrin ligands are key conserved regulators of axon guidance, and can function in a variety of signaling modes. Here we analyze the genetic and cellular requirements for Eph signaling in a Caenorhabditis elegans axon guidance choice point, the ventral guidance of axons in the amphid commissure. The C. elegans Eph receptor VAB-1 has both kinase-dependent and kinase-independent roles in amphid ventral guidance. Of the four C. elegans ephrins, we find that only EFN-1 has a major role in amphid axon ventral guidance, and signals in both a receptor kinase-dependent and kinase-independent manner. Analysis of VAB-1 and EFN-1 expression and tissue specific requirements is consistent with a model in which VAB-1 acts in amphid neurons, interacting with EFN-1 expressed on surrounding cells. Unexpectedly, left-hand neurons are more strongly affected than right-hand neurons by loss of Eph signaling, indicating a previously undetected left-right asymmetry in the requirement for Eph signaling. By screening candidate genes involved in Eph signaling we find that the Eph kinase-independent pathway involves the ABL-1 nonreceptor tyrosine kinase and possibly the phosphatidylinositol 3-kinase pathway. Overexpression of ABL-1 is sufficient to rescue vab-1 ventral guidance defects cell-autonomously. Our results reveal new aspects of Eph signaling in a single axon guidance decision in vivo.
    Full-text · Article · Aug 2013 · Genetics
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jan 2013 · Cell Research
Show more