David Traver

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

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Publications (85)1036.59 Total impact

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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 · 13.77 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 · 6.27 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 · 22.15 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 · 2.00 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 · 10.74 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 · 10.74 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.
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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 · 3.37 Impact Factor
  • Martin Distel, David Traver
    Cancer Research 10/2014; 74(20 Supplement):PR01-PR01. DOI:10.1158/1538-7445.PEDCAN-PR01 · 9.28 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 · 10.74 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; DOI:10.15252/embj.201488784 · 10.75 Impact Factor
  • David L Stachura, David Traver
    Blood 08/2014; 124(8):1204-6. DOI:10.1182/blood-2014-05-575415 · 10.43 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 · 42.35 Impact Factor
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    Experimental Hematology 08/2014; 42(8S):S6. DOI:10.1016/j.exphem.2014.07.019 · 2.81 Impact Factor
  • Experimental Hematology 08/2014; 42(8S):S13. DOI:10.1016/j.exphem.2014.07.044 · 2.81 Impact Factor
  • Experimental Hematology 08/2014; 42(8S):S19. DOI:10.1016/j.exphem.2014.07.066 · 2.81 Impact Factor
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    ABSTRACT: Despite progress in identifying the cellular composition of hematopoietic stem/progenitor cell (HSPC) niches, little is known about the molecular requirements of HSPC support. To address this issue, we used a panel of 6 recognized HSPC-­‐supportive stromal lines and less-­‐supportive counterparts originating from embryonic and adult hematopoietic sites. Through comprehensive transcriptomic meta-­‐analyses, we identified 481 mRNAs and 17 microRNAs organized in a modular network implicated in paracrine signaling. Further inclusion of 18 additional cell strains demonstrated that this mRNA subset was predictive of HSPC support. Our gene set contains most known HSPC regulators but also a number of novel ones, such as Pax9 and Ccdc80, as validated by functional studies in zebrafish embryos. In sum, our approach has identified the core molecular network required for HSPC support. These cues together with a searchable web resource will inform ongoing efforts to instruct HSPC ex vivo amplification and formation from pluripotent precursors.
    Cell Stem Cell 07/2014; 15(3). DOI:10.1016/j.stem.2014.06.005 · 22.15 Impact Factor
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    ABSTRACT: In non-mammalian vertebrates, the functional units of hemostasis are thrombocytes. Thrombocytes are thought to arise from bi-potent thrombocytic/erythroid progenitors (TEPs). TEPs have been experimentally demonstrated in avian models of hematopoiesis, and mammals possess functional equivalents known as megakaryocyte/erythroid progenitors (MEPs). However, the presence of TEPs in teleosts has only been speculated. To identify and prospectively isolate TEPs, we identified, cloned, and generated recombinant zebrafish thrombopoietin (Tpo). Tpo mRNA expanded itga2b:GFP(+) (cd41:GFP(+)) thrombocytes as well as hematopoietic stem and progenitor cells (HSPCs) in the zebrafish embryo. Utilizing Tpo in clonal methylcellulose assays, we describe for the first time the prospective isolation and characterization of TEPs from transgenic zebrafish. Combinatorial use of zebrafish Tpo, erythropoietin (Epo), and granulocyte colony stimulating factor (Gcsf) allowed the investigation of HSPCs responsible for erythro-, myelo-, and thrombo-poietic differentiation. Utilizing these assays allowed the visualization and differentiation of hematopoietic progenitors ex vivo in real-time with time-lapse and high-throughput microscopy, allowing analyses of their clonogenic and proliferative capacity. These studies indicate that the functional role of Tpo in the differentiation of thrombocytes from HSPCs is well conserved among vertebrate organisms, positing the zebrafish as an excellent model to investigate diseases caused by dysregulated erythro- and thrombo-poietic differentiation.
    Blood 05/2014; 124(2). DOI:10.1182/blood-2014-03-564682 · 10.43 Impact Factor
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    ABSTRACT: Antigen presentation is a critical step in the activation of naïve T lymphocytes. In mammals, dendritic cells (DCs), macrophages, and B lymphocytes can all function as antigen presenting cells (APCs). Although APCs have been identified in zebrafish, it is unclear if they fulfill similar roles in the initiation of adaptive immunity. Here we review the characterization of zebrafish macrophages, DCs, and B cells and evidence of their function as true APCs. Finally, we discuss the conservation of APC activity in vertebrates and the use of zebrafish to provide a new perspective on the evolution of these functions.
    Developmental and comparative immunology 03/2014; DOI:10.1016/j.dci.2014.03.010 · 3.71 Impact Factor
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    ABSTRACT: Granulocyte colony stimulating factor (Gcsf) drives the proliferation and differentiation of granulocytes, monocytes, and macrophages (ms) from hematopoietic stem and progenitor cells (HSPCs). Analysis of the zebrafish genome indicates the presence of two Gcsf ligands, likely resulting from a duplication event in teleost evolution. Although Gcsfa and Gcsfb share low sequence conservation, they share significant similarity in their predicted ligand/receptor interaction sites and structure. Each ligand displays differential temporal expression patterns during embryogenesis and spatial expression patterns in adult animals. To determine the functions of each ligand, we performed loss- and gain-of-function experiments. Both ligands signal through the Gcsf receptor to expand primitive neutrophils and ms, as well as definitive granulocytes. To further address their functions, we generated recombinant versions, and tested them in clonal progenitor assays. These sensitive in vitro techniques indicated similar functional attributes in supporting HSPC growth and differentiation. Finally, in addition to supporting myeloid differentiation, zebrafish Gcsf is required for the specification and proliferation of hematopoietic stem cells (HSCs), suggesting that Gcsf represents an ancestral cytokine responsible for the broad support of HSPCs. These findings may inform how hematopoietic cytokines evolved following the diversification of teleosts and mammals from a common ancestor.
    Blood 10/2013; 122(24). DOI:10.1182/blood-2012-12-475392 · 10.43 Impact Factor

Publication Stats

7k Citations
1,036.59 Total Impact Points

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  • 2006–2015
    • University of California, San Diego
      • • Department of Cellular and Molecular Medicine (CMM)
      • • Division of Biological Sciences
      • • Section of Cell and Developmental Biology
      San Diego, California, United States
  • 2013
    • St. Jude Children's Research Hospital
      • Division of Experimental Hematology
      Memphis, TN, United States
  • 2004–2005
    • Dana-Farber Cancer Institute
      • Department of Cancer Immunology and AIDS
      Boston, Massachusetts, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2003–2005
    • Boston Children's Hospital
      • Department of Pediatrics
      Boston, Massachusetts, United States
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Stanford Medicine
      Stanford, California, United States
  • 2002–2004
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1998–2000
    • Stanford University
      • • Department of Pathology
      • • Department of Developmental Biology
      Stanford, CA, United States