GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE92357 | GEO | 2017/03/09
SECONDARY ACCESSION(S): PRJNA357286
REPOSITORIES: GEO
Similar Datasets
Project description:Microvascular endothelial cells (ECs) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Microvascular ECs instruct neighboring cells in their organ-specific vascular niches through angiocrine factors, which include secreted growth factors (angiokines), extracellular matrix molecules, and transmembrane proteins. However, the molecular regulators that drive organ-specific microvascular transcriptional programs and thereby regulate angiodiversity are largely elusive. In contrast to other ECs, which form a continuous cell layer, liver sinusoidal ECs (LSECs) constitute discontinuous, permeable microvessels. Here, we have shown that the transcription factor GATA4 controls murine LSEC specification and function. LSEC-restricted deletion of Gata4 caused transformation of discontinuous liver sinusoids into continuous capillaries. Capillarization was characterized by ectopic basement membrane deposition, formation of a continuous EC layer, and increased expression of VE-cadherin. Correspondingly, ectopic expression of GATA4 in cultured continuous ECs mediated the downregulation of continuous EC-associated transcripts and upregulation of LSEC-associated genes. The switch from discontinuous LSECs to continuous ECs during embryogenesis caused liver hypoplasia, fibrosis, and impaired colonization by hematopoietic progenitor cells, resulting in anemia and embryonic lethality. Thus, GATA4 acts as master regulator of hepatic microvascular specification and acquisition of organ-specific vascular competence, which are indispensable for liver development. The data also establish an essential role of the hepatic microvasculature in embryonic hematopoiesis.
| S-EPMC5330741 | biostudies-literature
Project description:Microvascular endothelial cells (EC) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Microvascular EC instruct neighboring cells in their organ-specific vascular niches by angiocrine factors that comprise secreted growth factors/angiokines, but also extracellular matrix molecules and transmembrane proteins. The molecular regulators, however, that drive organ-specific microvascular transcriptional programs and thereby regulate angiodiversity, are largely elusive. Opposite to continuous barrier-forming EC, liver sinusoids are a prime model of discontinuous, permeable micro-vessels. Here, we show that transcription factor GATA4 controls liver sinusoidal endothelial (LSEC) specification and function. LSEC-restricted deletion of GATA4 caused transformation of discontinuous liver sinusoids into continuous capillaries. Capillarization was characterized by ectopic basement membrane deposition and formation of an abundantly VE-Cadherin expressing continuous endothelium. Correspondingly, ectopic expression of GATA4 in cultured continuous EC mediated downregulation of continuous EC transcripts and upregulation of LSEC genes. Regarding angiocrine functions, the switch from discontinuous LSEC to continuous EC during embryogenesis caused liver hypoplasia, fibrosis, and impaired colonization by hematopoietic progenitor cells resulting in anemia and embryonic lethality. Thus, GATA4 acts as master regulator of hepatic microvascular specification and acquisition of organ-specific vascular competence indispensable for liver development. The data also establish an essential role of the hepatic microvasculature for embryonic hematopoiesis.
2017-03-09 | GSE92356 | GEO
Project description:Microvascular endothelial cells (EC) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Microvascular EC instruct neighboring cells in their organ-specific vascular niches by angiocrine factors that comprise secreted growth factors/angiokines, but also extracellular matrix molecules and transmembrane proteins. The molecular regulators, however, that drive organ-specific microvascular transcriptional programs and thereby regulate angiodiversity, are largely elusive. Opposite to continuous barrier-forming EC, liver sinusoids are a prime model of discontinuous, permeable micro-vessels. Here, we show that transcription factor GATA4 controls liver sinusoidal endothelial (LSEC) specification and function. LSEC-restricted deletion of GATA4 caused transformation of discontinuous liver sinusoids into continuous capillaries. Capillarization was characterized by ectopic basement membrane deposition and formation of an abundantly VE-Cadherin expressing continuous endothelium. Correspondingly, ectopic expression of GATA4 in cultured continuous EC mediated downregulation of continuous EC transcripts and upregulation of LSEC genes. Regarding angiocrine functions, the switch from discontinuous LSEC to continuous EC during embryogenesis caused liver hypoplasia, fibrosis, and impaired colonization by hematopoietic progenitor cells resulting in anemia and embryonic lethality. Thus, GATA4 acts as master regulator of hepatic microvascular specification and acquisition of organ-specific vascular competence indispensable for liver development. The data also establish an essential role of the hepatic microvasculature for embryonic hematopoiesis.
2017-03-09 | GSE92354 | GEO
Project description:Microvascular endothelial cells (EC) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Microvascular EC instruct neighboring cells in their organ-specific vascular niches by angiocrine factors that comprise secreted growth factors/angiokines, but also extracellular matrix molecules and transmembrane proteins. The molecular regulators, however, that drive organ-specific microvascular transcriptional programs and thereby regulate angiodiversity, are largely elusive. Opposite to continuous barrier-forming EC, liver sinusoids are a prime model of discontinuous, permeable micro-vessels. Here, we show that transcription factor GATA4 controls liver sinusoidal endothelial (LSEC) specification and function. LSEC-restricted deletion of GATA4 caused transformation of discontinuous liver sinusoids into continuous capillaries. Capillarization was characterized by ectopic basement membrane deposition and formation of an abundantly VE-Cadherin expressing continuous endothelium. Correspondingly, ectopic expression of GATA4 in cultured continuous EC mediated downregulation of continuous EC transcripts and upregulation of LSEC genes. Regarding angiocrine functions, the switch from discontinuous LSEC to continuous EC during embryogenesis caused liver hypoplasia, fibrosis, and impaired colonization by hematopoietic progenitor cells resulting in anemia and embryonic lethality. Thus, GATA4 acts as master regulator of hepatic microvascular specification and acquisition of organ-specific vascular competence indispensable for liver development. The data also establish an essential role of the hepatic microvasculature for embryonic hematopoiesis.
2017-03-09 | GSE92352 | GEO
Project description:GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis
| PRJNA357286 | ENA
Project description:The blast colony-forming cell (BL-CFC) was identified as an equivalent to the hemangioblast during in vitro embryonic stem (ES) cell differentiation. However, the molecular mechanisms underlying the generation of the BL-CFC remain largely unknown. Here we report the isolation of mouse lysocardiolipin acyltransferase (Lycat) based on homology to zebrafish lycat, a candidate gene for the cloche locus. Mouse Lycat is expressed in hematopoietic organs and is enriched in the Lin(-)C-Kit(+)Sca-1(+) hematopoietic stem cells in bone marrow and in the Flk1(+)/hCD4(+)(Scl(+)) hemangioblast population in embryoid bodies. The forced Lycat transgene leads to increased messenger RNA expression of hematopoietic and endothelial genes as well as increased blast colonies and their progenies, endothelial and hematopoietic lineages. The Lycat small interfering RNA transgene leads to a decrease expression of hematopoietic and endothelial genes. An unbiased genomewide microarray analysis further substantiates that the forced Lycat transgene specifically up-regulates a set of genes related to hemangioblasts and hematopoietic and endothelial lineages. Therefore, mouse Lycat plays an important role in the early specification of hematopoietic and endothelial cells, probably acting at the level of the hemangioblast.
| S-EPMC2077310 | biostudies-literature
Project description:BACKGROUND:Although c-Kit+ adult progenitor cells were initially reported to produce new cardiomyocytes in the heart, recent genetic evidence suggests that such events are exceedingly rare. However, to determine if these rare events represent true de novo cardiomyocyte formation, we deleted the necessary cardiogenic transcription factors Gata4 and Gata6 from c-Kit-expressing cardiac progenitor cells. METHODS:Kit allele-dependent lineage tracing and fusion analysis were performed in mice following simultaneous Gata4 and Gata6 cell type-specific deletion to examine rates of putative de novo cardiomyocyte formation from c-Kit+ cells. Bone marrow transplantation experiments were used to define the contribution of Kit allele-derived hematopoietic cells versus Kit lineage-dependent cells endogenous to the heart in contributing to apparent de novo lineage-traced cardiomyocytes. A Tie2CreERT2 transgene was also used to examine the global impact of Gata4 deletion on the mature cardiac endothelial cell network, which was further evaluated with select angiogenesis assays. RESULTS:Deletion of Gata4 in Kit lineage-derived endothelial cells or in total endothelial cells using the Tie2CreERT2 transgene, but not from bone morrow cells, resulted in profound endothelial cell expansion, defective endothelial cell differentiation, leukocyte infiltration into the heart, and a dramatic increase in Kit allele-dependent lineage-traced cardiomyocytes. However, this increase in labeled cardiomyocytes was an artefact of greater leukocyte-cardiomyocyte cellular fusion because of defective endothelial cell differentiation in the absence of Gata4. CONCLUSIONS:Past identification of presumed de novo cardiomyocyte formation in the heart from c-Kit+ cells using Kit allele lineage tracing appears to be an artefact of labeled leukocyte fusion with cardiomyocytes. Deletion of Gata4 from c-Kit+ endothelial progenitor cells or adult endothelial cells negatively impacted angiogenesis and capillary network integrity.
| S-EPMC6125755 | biostudies-literature
Project description:In the mammalian liver, bile is transported to the intestine through an intricate network of bile ducts. Notch signaling is required for normal duct formation, but its mode of action has been unclear. Here, we show in mice that bile ducts arise through a novel mechanism of tubulogenesis involving sequential radial differentiation. Notch signaling is activated in a subset of liver progenitor cells fated to become ductal cells, and pathway activation is necessary for biliary fate. Notch signals are also required for bile duct morphogenesis, and activation of Notch signaling in the hepatic lobule promotes ectopic biliary differentiation and tubule formation in a dose-dependent manner. Remarkably, activation of Notch signaling in postnatal hepatocytes causes them to adopt a biliary fate through a process of reprogramming that recapitulates normal bile duct development. These results reconcile previous conflicting reports about the role of Notch during liver development and suggest that Notch acts by coordinating biliary differentiation and morphogenesis.
| S-EPMC2673761 | biostudies-literature
Project description:The oncogenic transcription factor Runx1 is required for the specification of definitive hematopoietic stem cells (HSC) in the developing embryo. The activity of this master regulator is tightly controlled during development. The transcription factors that upregulate the expression of Runx1 also upregulate the expression of Smad6, the inhibitory Smad, which controls Runx1 activity by targeting it to the proteasome. Here we show that Runx1, in conjunction with Fli1, Gata2, and Scl, directly regulates the expression of Smad6 in the aorta-gonad-mesonephros (AGM) region in the developing embryo, where HSCs originate. Runx1 regulates Smad6 activity via a novel upstream enhancer, and Runx1 null embryos show reduced Smad6 transcripts in the yolk-sac and c-Kit-positive fetal liver cells. By directly regulating the expression of Smad6, Runx1 sets up a functional rheostat to control its own activity. The perturbation of this rheostat, using a proteasomal inhibitor, results in an increase in Runx1 and Smad6 levels that can be directly attributed to increased Runx1 binding to tissue-specific regulatory elements of these genes. Taken together, we describe a scenario in which a key hematopoietic transcription factor controls its own expression levels by transcriptionally controlling its controller.
| S-EPMC3133398 | biostudies-literature
Project description:Membrane properties are emerging as important cues for the spatiotemporal regulation of hormone signaling. Lysophosphatidic acid (LPA) evokes multiple biological responses by activating G protein-coupled receptors in mammals. In this study, we demonstrated that LPA derived from the mitochondrial glycerol-3-phosphate acyltransferases GPAT1 and GPAT2 is a critical lipid-based cue for auxin-controlled embryogenesis and plant growth in Arabidopsis thaliana. LPA levels decreased, and the polarity of the auxin efflux carrier PIN-FORMED1 (PIN1) at the plasma membrane (PM) was defective in the gpat1 gpat2 mutant. As a consequence of distribution defects, instructive auxin gradients and embryonic and postembryonic development are severely compromised. Further cellular and genetic analyses revealed that LPA binds directly to PIN1, facilitating the vesicular trafficking of PIN1 and polar auxin transport. Our data support a model in which LPA provides a lipid landmark that specifies membrane identity and cell polarity, revealing an unrecognized aspect of phospholipid patterns connecting hormone signaling with development.
| S-EPMC9894262 | biostudies-literature