David Traver

University of California, San Diego, San Diego, California, United States

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Publications (90)844.31 Total impact

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    ABSTRACT: The IL-2 receptor γ common (IL-2Rγc) chain is the shared subunit of the receptors for the IL-2 family of cytokines, which mediate signaling through JAK3 and various downstream pathways to regulate lymphopoiesis. Inactivating mutations in human IL-2Rγc result in SCID, a primary immunodeficiency characterized by greatly reduced numbers of lymphocytes. This study used bioinformatics, expression analysis, gene ablation, and specific pharmacologic inhibitors to investigate the function of two putative zebrafish IL-2Rγc paralogs, il-2rγc.a and il-2rγc.b, and downstream signaling components during early lymphopoiesis. Expression of il-2rγc.a commenced at 16 h post fertilization (hpf) and rose steadily from 4-6 d postfertilization (dpf) in the developing thymus, with il-2rγc.a expression also confirmed in adult T and B lymphocytes. Transcripts of il-2rγc.b were first observed from 8 hpf, but waned from 16 hpf before reaching maximal expression at 6 dpf, but this was not evident in the thymus. Knockdown of il-2rγc.a, but not il-2rγc.b, substantially reduced embryonic lymphopoiesis without affecting other aspects of hematopoiesis. Specific targeting of zebrafish Jak3 exerted a similar effect on lymphopoiesis, whereas ablation of zebrafish Stat5.1 and pharmacologic inhibition of PI3K and MEK also produced significant but smaller effects. Ablation of il-2rγc.a was further demonstrated to lead to an absence of mature T cells, but not B cells in juvenile fish. These results indicate that conserved IL-2Rγc signaling via JAK3 plays a key role during early zebrafish lymphopoiesis, which can be potentially targeted to generate a zebrafish model of human SCID.
    The Journal of Immunology 11/2015; DOI:10.4049/jimmunol.1403060 · 4.92 Impact Factor
  • Emerald Butko · Claire Pouget · David Traver ·
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    ABSTRACT: Hematopoietic stem cells are formed during embryonic development, and serve as the foundation of the definitive blood program for life. Notch signaling has been well established as an essential direct contributor to HSC specification. However, several recent studies have indicated that the contribution of Notch signaling is complex. HSC specification requires multiple Notch signaling inputs, some received directly by hematopoietic precursors, and others that occur indirectly within neighboring somites. Of note, proinflammatory signals provided by primitive myeloid cells are needed for HSC specification via upregulation of the Notch pathway in hemogenic endothelium. In addition to multiple requirements for Notch activation, recent studies indicate that Notch signaling must subsequently be repressed to permit HSC emergence. Finally, Notch must then be reactivated to maintain HSC fate. In this review, we discuss the growing understanding of the dynamic contributions of Notch signaling to the establishment of hematopoiesis during development.
    Developmental Biology 11/2015; DOI:10.1016/j.ydbio.2015.11.008 · 3.55 Impact Factor
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    ABSTRACT: Forward genetic screens in zebrafish have been utilized to identify genes essential for the generation of primitive blood and the emergence of hematopoietic stem cells (HSCs), but have not elucidated genes essential for hematopoietic stem and progenitor cell (HSPC) proliferation and differentiation due to a lack of methodologies to functionally assess these processes. We previously described techniques to test the developmental potential of HSPCs by culturing them on zebrafish kidney stromal (ZKS) cells, derived from the main site of hematopoiesis in the adult teleost. Here we describe an additional primary stromal cell line we refer to as zebrafish embryonic stromal trunk (ZEST) cells, derived from tissue surrounding the embryonic dorsal aorta, the site of HSC emergence in developing fish. ZEST cells encouraged HSPC differentiation towards the myeloid, lymphoid, and erythroid pathways when assessed by morphological and qRT-PCR analyses. Additionally, ZEST cells significantly expanded the number of cultured HSPCs in vitro, indicating that these stromal cells are supportive of both HSPC proliferation and multilineage differentiation. Examination of ZEST cells indicates that they express numerous cytokines and Notch ligands, and possess endothelial characteristics. Further characterization of ZEST cells should prove to be invaluable in understanding the complex signaling cascades instigated by the embryonic hematopoietic niche required to expand and differentiate HSPCs. Elucidating these processes and identifying possibilities for the modulation of these molecular pathways should allow the in vitro expansion of HSPCs for a multitude of therapeutic uses.
    Experimental hematology 09/2015; DOI:10.1016/j.exphem.2015.09.001 · 2.48 Impact Factor
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    ABSTRACT: Bacterial meningitis is a serious infection of the CNS that results when blood-borne bacteria are able to cross the blood-brain barrier (BBB). Group B Streptococcus (GBS) is the leading cause of neonatal meningitis; however, the molecular mechanisms that regulate bacterial BBB disruption and penetration are not well understood. Here, we found that infection of human brain microvascular endothelial cells (hBMECs) with GBS and other meningeal pathogens results in the induction of host transcriptional repressor Snail1, which impedes expression of tight junction genes. Moreover, GBS infection also induced Snail1 expression in murine and zebrafish models. Tight junction components ZO-1, claudin 5, and occludin were decreased at both the transcript and protein levels in hBMECs following GBS infection, and this repression was dependent on Snail1 induction. Bacteria-independent Snail1 expression was sufficient to facilitate tight junction disruption, promoting BBB permeability to allow bacterial passage. GBS induction of Snail1 expression was dependent on the ERK1/2/MAPK signaling cascade and bacterial cell wall components. Finally, overexpression of a dominant-negative Snail1 homolog in zebrafish elevated transcription of tight junction protein-encoding genes and increased zebrafish survival in response to GBS challenge. Taken together, our data support a Snail1-dependent mechanism of BBB disruption and penetration by meningeal pathogens.
    The Journal of clinical investigation 05/2015; 125(6). DOI:10.1172/JCI74159 · 13.22 Impact Factor
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    David Traver ·

    Journal of Experimental Medicine 05/2015; 212(5):600. DOI:10.1084/jem.2125insight4 · 12.52 Impact Factor
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    ABSTRACT: The adult blood system is established by hematopoietic stem cells (HSCs), which arise during development from an endothelial-to-hematopoietic transition of cells comprising the floor of the dorsal aorta. Expression of aortic runx1 has served as an early marker of HSC commitment in the zebrafish embryo, but recent studies have suggested that HSC specification begins during the convergence of posterior lateral plate mesoderm (PLM), well before aorta formation and runx1 transcription. Further understanding of the earliest stages of HSC specification necessitates an earlier marker of hemogenic endothelium. Studies in mice have suggested that GATA2 might function at early stages within hemogenic endothelium. Two orthologs of Gata2 exist in zebrafish: gata2a and gata2b. Here, we report that gata2b expression initiates during the convergence of PLM, becoming restricted to emerging HSCs. We observe Notch-dependent gata2b expression within the hemogenic subcompartment of the dorsal aorta that is in turn required to initiate runx1 expression. Our results indicate that Gata2b functions within hemogenic endothelium from an early stage, whereas Gata2a functions more broadly throughout the vascular system. © 2015. Published by The Company of Biologists Ltd.
    Development 03/2015; 142(6):1050-61. DOI:10.1242/dev.119180 · 6.46 Impact Factor
  • Pankaj Sahai-Hernandez · David Traver ·
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    ABSTRACT: Stem cells reside in "niches," which provide signaling cues necessary for self-renewal. In a recent issue of Cell, Tamplin et al. (2015) perform live imaging of hematopoietic stem and progenitor cells (HSPCs) and find dynamic remodeling of endothelial cells is triggered upon arrival of HSPCs at the caudal hematopoietic tissue. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Stem Cell 02/2015; 16(2):109-110. DOI:10.1016/j.stem.2015.01.011 · 22.27 Impact Factor
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    ABSTRACT: Streptococcus agalactiae (Group B Streptococcus, GBS) is an encapsulated, Gram-positive bacterium that is a leading cause of neonatal pneumonia, sepsis and meningitis, and an emerging aquaculture pathogen. The zebrafish (Danio rerio) is a genetically tractable model vertebrate that has been used to analyze the pathogenesis of both aquatic and human bacterial pathogens. We have developed a larval zebrafish model of GBS infection to study bacterial and host factors that contribute to disease progression. GBS infection resulted in dose dependent larval death, and GBS serotype III, ST-17 strain was observed as the most virulent. Virulence was dependent on the presence of the GBS capsule, surface anchored lipoteichoic acid (LTA) and toxin production, as infection with GBS mutants lacking these factors resulted in little to no mortality. Additionally, interleukin-1β (il1b) and CXCL-8 (cxcl8a) were significantly induced following GBS infection compared to controls. We also visualized GBS outside the brain vasculature, suggesting GBS penetration into the brain during the course of infection. Our data demonstrate that zebrafish larvae are a valuable model organism to study GBS pathogenesis. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Microbial Pathogenesis 01/2015; 79C:57-60. DOI:10.1016/j.micpath.2015.01.007 · 1.79 Impact Factor
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    ABSTRACT: Haematopoietic stem cells (HSCs) are produced during embryogenesis from the floor of the dorsal aorta. The localization of HSCs is dependent on the presence of instructive signals on the ventral side of the vessel. The nature of the extrinsic molecular signals that control the aortic haematopoietic niche is currently poorly understood. Here we demonstrate a novel requirement for FGF signalling in the specification of aortic haemogenic endothelium. Our results demonstrate that FGF signalling normally acts to repress BMP activity in the subaortic mesenchyme through transcriptional inhibition of bmp4, as well as through activation of two BMP antagonists, noggin2 and gremlin1a. Taken together, these findings demonstrate a key role for FGF signalling in establishment of the developmental HSC niche via its regulation of BMP activity in the subaortic mesenchyme. These results should help inform strategies to recapitulate the development of HSCs in vitro from pluripotent precursors.
    Nature Communications 11/2014; 5:5588. DOI:10.1038/ncomms6588 · 11.47 Impact Factor
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    ABSTRACT: Haematopoietic stem cells (HSCs) derive from haemogenic endothelial cells of the primitive dorsal aorta (DA) during vertebrate embryogenesis. The molecular mechanisms governing this unique endothelial to haematopoietic transition remain unclear. Here, we demonstrate a novel requirement for fibroblast growth factor (FGF) signalling in HSC emergence. This requirement is non-cell-autonomous, and acts within the somite to bridge the Wnt and Notch signalling pathways. We previously demonstrated that Wnt16 regulates the somitic expression of two Notch ligands, deltaC (dlc) and deltaD (dld), whose combined function is required for HSC fate. How Wnt16 connects to Notch function has remained an open question. Our current studies demonstrate that FGF signalling, via FGF receptor 4 (Fgfr4), mediates a signal-transduction pathway between Wnt16 and Dlc, but not Dld, to regulate HSC specification. Our findings demonstrate that FGF signalling acts as a key molecular relay within the developmental HSC niche to instruct HSC fate.
    Nature Communications 11/2014; 5:5583. DOI:10.1038/ncomms6583 · 11.47 Impact Factor
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    ABSTRACT: Hematopoietic stem cells (HSCs) underlie the production of blood and immune cells for the lifetime of an organism. In vertebrate embryos, HSCs arise from the unique transdifferentiation of hemogenic endothelium comprising the floor of the dorsal aorta during a brief developmental window. To date, this process has not been replicated in vitro from pluripotent precursors, partly because the full complement of required signaling inputs remains to be determined. Here, we show that TNFR2 via TNF? activates the Notch and NF-?B signaling pathways to establish HSC fate, indicating a requirement for inflammatory signaling in HSC generation. We determine that primitive neutrophils are the major source of TNF?, assigning a role for transient innate immune cells in establishing the HSC program. These results demonstrate that proinflammatory signaling, in the absence of infection, is utilized by the developing embryo to generate the lineal precursors of the adult hematopoietic system.
    Cell 11/2014; 159(5):1070-85. DOI:10.1016/j.cell.2014.10.031 · 32.24 Impact Factor
  • Albert D Kim · David L Stachura · David Traver ·
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    ABSTRACT: Generation of hematopoietic stem cells is a pressing goal for regenerative medicine.•The ontogeny of the hematopoietic system proceeds through multiple waves.•Hematopoietic stem cell formation requires inputs from multiple cell signaling pathways during embryonic development.•Current advancements in the generation of hematopoietic stem cells are discussed.
    Experimental Cell Research 10/2014; 329(2). DOI:10.1016/j.yexcr.2014.10.011 · 3.25 Impact Factor
  • Martin Distel · David Traver ·

    Cancer Research 10/2014; 74(20 Supplement):PR01-PR01. DOI:10.1158/1538-7445.PEDCAN-PR01 · 9.33 Impact Factor
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    ABSTRACT: Calcium ions (Ca(2+)) function as universal second messengers in eukaryotic cells, including immune cells. Ca(2+) is crucial for peripheral T-lymphocyte activation and effector functions, and influences thymocyte selection and motility in the developing thymus. However, the role of Ca(2+) signalling in early T-lymphocyte development is not well understood. Here we show that the inositol triphosphate receptors (IP3Rs) Ca(2+) ion channels are required for proliferation, survival and developmental progression of T-lymphocyte precursors. Our studies indicate that signalling via IP3Rs represses Sox13, an antagonist of the developmentally important transcription factor Tcf-1. In the absence of IP3R-mediated Ca(2+) signalling, repression of key Notch transcriptional targets-including Hes1-fail to occur in post β-selection thymocytes, and mice develop aggressive T-cell malignancies that resemble human T-cell acute lymphoblastic leukemia (T-ALL). These data indicate that IP3R-mediated Ca(2+) signalling reinforces Tcf-1 activity to both ensure normal development and prevent thymocyte neoplasia.
    Nature Communications 09/2014; 5:4814. DOI:10.1038/ncomms5814 · 11.47 Impact Factor
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    ABSTRACT: Hematopoietic stem cells (HSCs) require multiple molecular inputs for proper specification, including activity of the Notch signaling pathway. A requirement for the Notch1 and dispensability of the Notch2 receptor has been demonstrated in mice, but the role of the remaining Notch receptors has not been investigated. Here, we demonstrate that three of the four Notch receptors are independently required for the specification of HSCs in the zebrafish. The orthologues of the murine Notch1 receptor, Notch1a and Notch1b, are each required intrinsically to fate HSCs, just prior to their emergence from aortic hemogenic endothelium. By contrast, the Notch3 receptor is required earlier within the developing somite to regulate HSC emergence in a non-cell-autonomous manner. Epistatic analyses demonstrate that Notch3 function lies downstream of Wnt16, which is required for HSC specification through its regulation of two Notch ligands, dlc and dld. Collectively, these findings demonstrate for the first time that multiple Notch signaling inputs are required to specify HSCs and that Notch3 performs a novel role within the somite to regulate the neighboring precursors of hemogenic endothelium.
    The EMBO Journal 09/2014; 33(20). DOI:10.15252/embj.201488784 · 10.43 Impact Factor
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    David L Stachura · David Traver ·
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    ABSTRACT: In this issue of Blood, Lopez et al undertake the heroic task of characterizing the blood-forming system of the axolotl (Ambystoma mexicanum), an aquatic salamander that provides an excellent model for tissue regeneration and scar-free wound healing.1 Commonly referred to as the "Mexican walking fish," axolotls are not fish at all, but rather neotenic salamanders that retain many larval traits throughout their lifespan because they do not undergo a typical juvenile to adult metamorphosis. This retention of larval traits is associated with the profound ability of the axolotl to regenerate many of its tissues, including limbs, spinal cord, heart, and even parts of its brain.
    Blood 08/2014; 124(8):1204-6. DOI:10.1182/blood-2014-05-575415 · 10.45 Impact Factor
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    ABSTRACT: Notch signalling plays a key role in the generation of haematopoietic stem cells (HSCs) during vertebrate development and requires intimate contact between signal-emitting and signal-receiving cells, although little is known regarding when, where and how these intercellular events occur. We previously reported that the somitic Notch ligands, Dlc and Dld, are essential for HSC specification. It has remained unclear, however, how these somitic requirements are connected to the later emergence of HSCs from the dorsal aorta. Here we show in zebrafish that Notch signalling establishes HSC fate as their shared vascular precursors migrate across the ventral face of the somite and that junctional adhesion molecules (JAMs) mediate this required Notch signal transduction. HSC precursors express jam1a (also known as f11r) and migrate axially across the ventral somite, where Jam2a and the Notch ligands Dlc and Dld are expressed. Despite no alteration in the expression of Notch ligand or receptor genes, loss of function of jam1a led to loss of Notch signalling and loss of HSCs. Enforced activation of Notch in shared vascular precursors rescued HSCs in jam1a or jam2a deficient embryos. Together, these results indicate that Jam1a-Jam2a interactions facilitate the transduction of requisite Notch signals from the somite to the precursors of HSCs, and that these events occur well before formation of the dorsal aorta.
    Nature 08/2014; 512(7514). DOI:10.1038/nature13623 · 41.46 Impact Factor
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    Experimental hematology; 08/2014

  • Experimental Hematology 08/2014; 42(8S):S19. DOI:10.1016/j.exphem.2014.07.066 · 2.48 Impact Factor

  • Experimental Hematology 08/2014; 42(8S):S13. DOI:10.1016/j.exphem.2014.07.044 · 2.48 Impact Factor

Publication Stats

8k Citations
844.31 Total Impact Points

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  • 2006-2015
    • University of California, San Diego
      • • Department of Cellular and Molecular Medicine (CMM)
      • • Section of Cell and Developmental Biology
      San Diego, California, United States
  • 2013
    • University of the Pacific (California - USA)
      Stockton, California, United States
  • 2011
    • University of Miami
      • Department of Medicine
      Coral Gables, FL, United States
  • 2003-2009
    • Boston Children's Hospital
      • Department of Pediatrics
      Boston, Massachusetts, United States
    • Stanford Medicine
      • Department of Medicine
      Stanford, California, United States
  • 2004
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2002-2003
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1998-2003
    • Stanford University
      • • Department of Pathology
      • • Department of Medicine
      • • Department of Developmental Biology
      Stanford, California, United States