Combinatorial function of ETS transcription factors in the developing vasculature

Laboratory of Molecular Genetics, National Institute of Child Health and Human Development/NIH, Building 6B, Room 309, 6 Center Drive, Bethesda, MD 20892, USA.
Developmental Biology (Impact Factor: 3.55). 04/2007; 303(2):772-83. DOI: 10.1016/j.ydbio.2006.10.030
Source: PubMed


Members of the ETS family of transcription factors are among the first genes expressed in the developing vasculature, but loss-of-function experiments for individual ETS factors in mice have not uncovered important early functional roles for these genes. However, multiple ETS factors are expressed in spatially and temporally overlapping patterns in the developing vasculature, suggesting possible functional overlap. We have taken a comprehensive approach to exploring the function of these factors during vascular development by employing the genetic and experimental tools available in the zebrafish to analyze four ETS family members expressed together in the zebrafish vasculature; fli1, fli1b, ets1, and etsrp. We isolated and characterized an ENU-induced mutant with defects in trunk angiogenesis and positionally cloned the defective gene from this mutant, etsrp. Using the etsrp morpholinos targeting each of the four genes, we show that the four ETS factors function combinatorially during vascular and hematopoietic development. Reduction of etsrp or any of the other genes alone results in either partial or no defects in endothelial differentiation, while combined reduction in the function of all four genes causes dramatic loss of endothelial cells. Our results demonstrate that combinatorial ETS factor function is essential for early endothelial specification and differentiation.

Download full-text


Available from: Daniel Castranova
  • Source
    • "In this regard, Warga et al. (2009) using a fate mapping approach argued that the posterior lateral plate mesoderm (PLPM) gives rise exclusively to neutrophils (Warga et al., 2009), while Jin et al. (2012) using a photo-labeling technique, proposed the anterior lateral plate mesoderm (ALPM) region as the origin of both macrophage and neutrophils (Jin et al., 2012). The discrepancy involving two anatomically separate regions was further solved through the independent spatial and temporal analysis in the expression of the critical transcription factors, scl (Dooley et al., 2005), gata1 (Glenn et al., 2014) and etv2 (Pham et al., 2007), in erythroid and myeloid development. Of particular interest was the observation that subsets of scl-expressing cells in both the ALPM and PLPM acquire a myeloid fate by expressing spi.1 or Etv2, which are two ETS-family transcription factors essential for myeloid development (Bennett et al., 2001; Glenn et al., 2014; Lieschke et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: To grant survival against sterile or microbe induced inflammation, all animals rely on correct immune system functioning. The development of immunity occurs in vertebrates during embryogenesis in a process called hematopoiesis, which is characterized by the formation of blood cellular components such as embryonic erythrocytes and primitive macrophages. These cells are formed in a sterile environment from a rare subset of pluripotent hematopoietic stem cells (HSC) during a brief period of the primitive hematopoietic wave. Diverse signals, like Notch, are indispensable in HSC emergence and differentiation. However, to successfully replicate the process in vitro using pluripotent precursors, the full set of required signals is still a matter of debate. Among the latest findings, proinflammatory signals produced by transient primitive myelocites in zebrafish have been seen to act as essential mediators in establishing the HSC program of the adult vertebrate hematopoietic system. In this regard, the zebrafish immune model has emerged as a feasible live vertebrate model for examining developmental immunity and related host-microbe interactions, both at the molecular and cellular level. Thus, using the zebrafish embryo, this review summarizes recent findings, on the signals required for immune development and further maturation of the system, in a context where no adaptive immune response has yet been developed.
    Full-text · Article · Nov 2015 · Molecular Immunology
  • Source
    • "Several zebrafish transcription factors that regulate hematopoiesis have been identified. The early stage markers gata2, lmo2, fli1, and scl (stem cell leukemia) are master regulators that are coexpressed in both the ALM and PLM, where hemangioblast development occurs, from the 2nd to the 3rd somite stages [20] [21] [23]. These genes are expressed in the PLM and later in the intermediate cell mass (ICM) [28– 31]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Myeloid malignancies are heterogeneous disorders characterized by uncontrolled proliferation or/and blockage of differentiation of myeloid progenitor cells. Although a substantial number of gene alterations have been identified, the mechanism by which these abnormalities interact has yet to be elucidated. Over the past decades, zebrafish have become an important model organism, especially in biomedical research. Several zebrafish models have been developed to recapitulate the characteristics of specific myeloid malignancies that provide novel insight into the pathogenesis of these diseases and allow the evaluation of novel small molecule drugs. This report will focus on illustrative examples of applications of zebrafish models, including transgenesis, zebrafish xenograft models, and cell transplantation approaches, to the study of human myeloid malignancies.
    Full-text · Article · Jun 2015 · BioMed Research International
  • Source
    • "Likewise, pdgfrb transcript was reduced in pdgfrb um148 mutant embryos and western blot analysis confirmed the absence of protein (Figures 2J and 2K). Embryos bearing mutations in amot, elmo1, and ets1 also displayed normal vascular patterning and circulatory function despite previous reports of defects in respective morphant embryos (Table S3; data not shown; Aase et al., 2007; Epting et al., 2010; Pham et al., 2007). In the case of the ets1 um206 mutation , we detected transcripts missing exon 3, which contains the um206 deletion, in heterozygous and mutant embryos (Figures 2L and 2M), while all remaining sequenced full-length transcripts bore the um206 deletion (data not shown). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The widespread availability of programmable site-specific nucleases now enables targeted gene disruption in the zebrafish. In this study, we applied site-specific nucleases to generate zebrafish lines bearing individual mutations in more than 20 genes. We found that mutations in only a small proportion of genes caused defects in embryogenesis. Moreover, mutants for ten different genes failed to recapitulate published Morpholino-induced phenotypes (morphants). The absence of phenotypes in mutant embryos was not likely due to maternal effects or failure to eliminate gene function. Consistently, a comparison of published morphant defects with the Sanger Zebrafish Mutation Project revealed that approximately 80% of morphant phenotypes were not observed in mutant embryos, similar to our mutant collection. Based on these results, we suggest that mutant phenotypes become the standard metric to define gene function in zebrafish, after which Morpholinos that recapitulate respective phenotypes could be reliably applied for ancillary analyses. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Dec 2014 · Developmental Cell
Show more