The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Martin L Breitman - One of the best experts on this subject based on the ideXlab platform.
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role of the flt 1 receptor tyrosine kinase in regulating the assembly of vascular endothelium
Nature, 1995Co-Authors: Guo Hua Fong, Janet Rossant, Marina Gertsenstein, Martin L BreitmanAbstract:The vascular endothelial growth factor (VEGF) and its high-affinity binding receptors, the tyrosine kinases Flt-1 and Flk-1, are thought to be important for the development of embryonic vasculature. Here we report that Flt-1 is essential for the organization of embryonic vasculature, but is not essential for endothelial cell differentiation. Mouse embryos homozygous for a targeted mutation in the flt-1 locus, flt-1lcz, formed endothelial cells in both embryonic and extra-embryonic regions, but assembled these cells into abnormal vascular channels and died in utero at mid-somite stages. At earlier stages, the Blood Islands of flt-1lcz homozygotes were abnormal, with angioblasts in the interior as well as on the periphery. We suggest that the Flt-1 signalling pathway may regulate normal endothelial cell-cell or cell-matrix interactions during vascular development.
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role of the flt 1 receptor tyrosine kinase in regulating the assembly of vascular endothelium
Nature, 1995Co-Authors: Guo Hua Fong, Janet Rossant, Marina Gertsenstein, Martin L BreitmanAbstract:THE vascular endothelial growth factor (VEGF) and its high-affinity binding receptors, the tyrosine kinases Flt-1 and Flk-1, are thought to be important for the development of embryonic vasculature1–8. Here we report that Flt-1 is essential for the organization of embryonic vasculature, but is not essential for endothelial cell differentiation. Mouse embryos homozygous for a targeted mutation in the flt-1 locus, flt-llcz formed endothelial cells in both embryonic and extra-embryonic regions, but assembled these cells into abnormal vascular channels and died in utero at mid-somite stages. At earlier stages, the Blood Islands of flt-llcz homozygotes were abnormal, with angioblasts in the interior as well as on the periphery. We suggest that the Flt-1 signalling pathway may regulate normal endothelial cell-cell or cell-matrix interactions during vascular development.
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failure of Blood island formation and vasculogenesis in flk 1 deficient mice
Nature, 1995Co-Authors: Fouad Shalaby, Janet Rossant, Marina Gertsenstein, Martin L Breitman, Terry P Yamaguchi, Xiangfu WuAbstract:THE receptor tyrosine kinase Flk-1 (ref. 1) is believed to play a pivotal role in endothelial development. Expression of the Flk-1 receptor is restricted to endothelial cells and their embryonic precursors2–5, and is complementary to that of its ligand, vascular endothelial growth factor (VEGF)2,3, which is an endothelial-speci-fic mitogen6. Highest levels of flk-1 expression are observed during embryonic vasculogenesis and angiogenesis2–5, and during pathological processes associated with neovascularization, such as tumour angiogenesis7,8. Because flk-1 expression can be detected in presumptive mesodermal yolk-sac Blood-island progenitors as early as 7.0 days postcoitum, Flk-1 may mark the putative common embryonic endothelial and haematopoietic precursor, the haemangioblast, and thus may also be involved in early haematopoiesis4. Here we report the generation of mice deficient in Flk-1 by disruption of the gene using homologous recombination in embryonic stem (ES) cells. Embryos homozygous for this mutation die in utero between 8.5 and 9.5 days post-coitum, as a result of an early defect in the development of haematopoietic and endothelial cells. Yolk-sac Blood Islands were absent at 7.5 days, organized Blood vessels could not be observed in the embryo or yolk sac at any stage, and haematopoietic progenitors were severely reduced. These results indicate that Flk-1 is essential for yolk-sac Blood-island formation and vasculogenesis in the mouse embryo.
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flk-1, an flt-related receptor tyrosine kinase is an early marker for endothelial cell precursors.
Development (Cambridge England), 1993Co-Authors: Terry P Yamaguchi, Martin L Breitman, Daniel J. Dumont, Ronald A. Conlon, Janet RossantAbstract:We have used RT-PCR to screen pluripotent murine embryonic stem cells to identify receptor tyrosine kinases (RTKs) potentially involved in the determination or differentiation of cell lineages during early mouse development. Fourteen different tyrosine kinase sequences were identified. The expression patterns of four RTKs have been examined and all are expressed in the mouse embryo during, or shortly after, gastrulation. We report here the detailed expression pattern of one such RTK, the flt-related gene flk-1. In situ hybridization analysis of the late primitive streak stage embryo revealed that flk-1 was expressed in the proximal-lateral embryonic mesoderm; tissue fated to become heart. By headfold stages, staining was confined to the endocardial cells of the heart primordia as well as to the Blood Islands of the visceral yolk sac and the developing allantois. Patchy, speckled staining was detected in the endothelium of all the major embryonic and extraembryonic Blood vessels as they formed. During early organogenesis, expression was detected in the Blood vessels of highly vascularized tissues such as the brain, liver, lungs and placenta. Since flk-1 was expressed in early mesodermal cells prior to any morphological evidence for endothelial cell differentiation (vasculogenesis), as well as in cells that form Blood vessels from preexisting ones (angiogenesis), it appears to be a very early marker of endothelial cell precursors. We have previously reported that another novel RTK, designated tek, was expressed in differentiating endothelial cells. We show here that flk-1 transcripts are expressed one full embryonic day earlier than the first tek transcripts. The expression of these two RTKs appear to correlate with the specification and early differentiation of the endothelial cell lineage respectively, and therefore may play important roles in the establishment of this lineage.
Janet Rossant - One of the best experts on this subject based on the ideXlab platform.
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a requirement for flk1 in primitive and definitive hematopoiesis and vasculogenesis
Cell, 1997Co-Authors: Fouad Shalaby, Andre C. Schuh, Jacqueline Ho, William L Stanford, Klausdieter Fischer, Lois Schwartz, Alan Bernstein, Janet RossantAbstract:Abstract Mouse embryos lacking the receptor tyrosine kinase, Flk1, die without mature endothelial and hematopoietic cells. To investigate the role of Flk1 during vasculogenesis and hematopoiesis, we examined the developmental potential of Flk1 −/− embryonic stem cells in chimeras. We show that Flk1 is required cell autonomously for endothelial development. Furthermore, Flk1 −/− cells do not contribute to primitive hematopoiesis in chimeric yolk sacs or definitive hematopoiesis in adult chimeras and chimeric fetal livers. We also demonstrate that cells lacking Flk1 are unable to reach the correct location to form Blood Islands, suggesting that Flk1 is involved in the movement of cells from the posterior primitive streak to the yolk sac and, possibly, to the intraembryonic sites of early hematopoiesis.
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role of the flt 1 receptor tyrosine kinase in regulating the assembly of vascular endothelium
Nature, 1995Co-Authors: Guo Hua Fong, Janet Rossant, Marina Gertsenstein, Martin L BreitmanAbstract:The vascular endothelial growth factor (VEGF) and its high-affinity binding receptors, the tyrosine kinases Flt-1 and Flk-1, are thought to be important for the development of embryonic vasculature. Here we report that Flt-1 is essential for the organization of embryonic vasculature, but is not essential for endothelial cell differentiation. Mouse embryos homozygous for a targeted mutation in the flt-1 locus, flt-1lcz, formed endothelial cells in both embryonic and extra-embryonic regions, but assembled these cells into abnormal vascular channels and died in utero at mid-somite stages. At earlier stages, the Blood Islands of flt-1lcz homozygotes were abnormal, with angioblasts in the interior as well as on the periphery. We suggest that the Flt-1 signalling pathway may regulate normal endothelial cell-cell or cell-matrix interactions during vascular development.
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role of the flt 1 receptor tyrosine kinase in regulating the assembly of vascular endothelium
Nature, 1995Co-Authors: Guo Hua Fong, Janet Rossant, Marina Gertsenstein, Martin L BreitmanAbstract:THE vascular endothelial growth factor (VEGF) and its high-affinity binding receptors, the tyrosine kinases Flt-1 and Flk-1, are thought to be important for the development of embryonic vasculature1–8. Here we report that Flt-1 is essential for the organization of embryonic vasculature, but is not essential for endothelial cell differentiation. Mouse embryos homozygous for a targeted mutation in the flt-1 locus, flt-llcz formed endothelial cells in both embryonic and extra-embryonic regions, but assembled these cells into abnormal vascular channels and died in utero at mid-somite stages. At earlier stages, the Blood Islands of flt-llcz homozygotes were abnormal, with angioblasts in the interior as well as on the periphery. We suggest that the Flt-1 signalling pathway may regulate normal endothelial cell-cell or cell-matrix interactions during vascular development.
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failure of Blood island formation and vasculogenesis in flk 1 deficient mice
Nature, 1995Co-Authors: Fouad Shalaby, Janet Rossant, Marina Gertsenstein, Martin L Breitman, Terry P Yamaguchi, Xiangfu WuAbstract:THE receptor tyrosine kinase Flk-1 (ref. 1) is believed to play a pivotal role in endothelial development. Expression of the Flk-1 receptor is restricted to endothelial cells and their embryonic precursors2–5, and is complementary to that of its ligand, vascular endothelial growth factor (VEGF)2,3, which is an endothelial-speci-fic mitogen6. Highest levels of flk-1 expression are observed during embryonic vasculogenesis and angiogenesis2–5, and during pathological processes associated with neovascularization, such as tumour angiogenesis7,8. Because flk-1 expression can be detected in presumptive mesodermal yolk-sac Blood-island progenitors as early as 7.0 days postcoitum, Flk-1 may mark the putative common embryonic endothelial and haematopoietic precursor, the haemangioblast, and thus may also be involved in early haematopoiesis4. Here we report the generation of mice deficient in Flk-1 by disruption of the gene using homologous recombination in embryonic stem (ES) cells. Embryos homozygous for this mutation die in utero between 8.5 and 9.5 days post-coitum, as a result of an early defect in the development of haematopoietic and endothelial cells. Yolk-sac Blood Islands were absent at 7.5 days, organized Blood vessels could not be observed in the embryo or yolk sac at any stage, and haematopoietic progenitors were severely reduced. These results indicate that Flk-1 is essential for yolk-sac Blood-island formation and vasculogenesis in the mouse embryo.
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flk-1, an flt-related receptor tyrosine kinase is an early marker for endothelial cell precursors.
Development (Cambridge England), 1993Co-Authors: Terry P Yamaguchi, Martin L Breitman, Daniel J. Dumont, Ronald A. Conlon, Janet RossantAbstract:We have used RT-PCR to screen pluripotent murine embryonic stem cells to identify receptor tyrosine kinases (RTKs) potentially involved in the determination or differentiation of cell lineages during early mouse development. Fourteen different tyrosine kinase sequences were identified. The expression patterns of four RTKs have been examined and all are expressed in the mouse embryo during, or shortly after, gastrulation. We report here the detailed expression pattern of one such RTK, the flt-related gene flk-1. In situ hybridization analysis of the late primitive streak stage embryo revealed that flk-1 was expressed in the proximal-lateral embryonic mesoderm; tissue fated to become heart. By headfold stages, staining was confined to the endocardial cells of the heart primordia as well as to the Blood Islands of the visceral yolk sac and the developing allantois. Patchy, speckled staining was detected in the endothelium of all the major embryonic and extraembryonic Blood vessels as they formed. During early organogenesis, expression was detected in the Blood vessels of highly vascularized tissues such as the brain, liver, lungs and placenta. Since flk-1 was expressed in early mesodermal cells prior to any morphological evidence for endothelial cell differentiation (vasculogenesis), as well as in cells that form Blood vessels from preexisting ones (angiogenesis), it appears to be a very early marker of endothelial cell precursors. We have previously reported that another novel RTK, designated tek, was expressed in differentiating endothelial cells. We show here that flk-1 transcripts are expressed one full embryonic day earlier than the first tek transcripts. The expression of these two RTKs appear to correlate with the specification and early differentiation of the endothelial cell lineage respectively, and therefore may play important roles in the establishment of this lineage.
Irving L. Weissman - One of the best experts on this subject based on the ideXlab platform.
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Myeloid Cell Origins, Differentiation, and Clinical Implications.
Myeloid Cells in Health and Disease, 2017Co-Authors: Kipp Weiskopf, Irving L. Weissman, Peter J. Schnorr, Wendy W. Pang, Mark P. Chao, Akanksha Chhabra, Jun Seita, Mingye FengAbstract:The hematopoietic stem cell (HSC) is a multipotent stem cell that resides in the bone marrow and has the ability to form all of the cells of the Blood and immune system. Since its first purification in 1988, additional studies have refined the phenotype and functionality of HSCs and characterized all of their downstream progeny. The hematopoietic lineage is divided into two main branches: the myeloid and lymphoid arms. The myeloid arm is characterized by the common myeloid progenitor and all of its resulting cell types. The stages of hematopoiesis have been defined in both mice and humans. During embryological development, the earliest hematopoiesis takes place in yolk sac Blood Islands and then migrates to the fetal liver and hematopoietic organs. Some adult myeloid populations develop directly from yolk sac progenitors without apparent bone marrow intermediates, such as tissue-resident macrophages. Hematopoiesis also changes over time, with a bias of the dominating HSCs toward myeloid development as animals age. Defects in myelopoiesis contribute to many hematologic disorders, and some of these can be overcome with therapies that target the aberrant stage of development. Furthermore, insights into myeloid development have informed us of mechanisms of programmed cell removal. The CD47/SIRPα axis, a myeloid-specific immune checkpoint, limits macrophage removal of HSCs but can be exploited by hematologic and solid malignancies. Therapeutics targeting CD47 represent a new strategy for treating cancer. Overall, an understanding of hematopoiesis and myeloid cell development has implications for regenerative medicine, hematopoietic cell transplantation, malignancy, and many other diseases.
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clonal analysis of mouse development reveals a polyclonal origin for yolk sac Blood Islands
Developmental Cell, 2006Co-Authors: Hiroo Ueno, Irving L. WeissmanAbstract:Direct clonal analysis of tissue and organ maturation in vivo is a critical step in the interpretation of in vitro cell precursor-progeny relationships. We have developed a method to analyze clonal progenitor contributions in vivo using ES cells stably expressing separate fluorescent proteins and placed into normal blastocysts to form tetrachimeras. Here we applied this method to the analysis of embryonic yolk sac Blood Islands. In most vertebrates, yolk sac Blood Islands are the initial sites of appearance of hematopoietic and endothelial cells. It has been proposed that these lineages arise from a common clonal progenitor, the hemangioblast, but this hypothesis has not been tested directly in physiological development in vivo. Our analysis shows that each island has contributions from multiple progenitors. Moreover, contribution by individual hemangioblast progenitors to both endothelial and hematopoietic lineages within an island, if it happens at all, is an infrequent event.
Mitsugu Maeno - One of the best experts on this subject based on the ideXlab platform.
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nkx2 5 is involved in myeloid cell differentiation at anterior ventral Blood Islands in the xenopus embryo
Development Growth & Differentiation, 2014Co-Authors: Hiroyuki Sakata, Mitsugu MaenoAbstract:We have shown previously that two populations of myeloid cells emerge in the anterior and posterior ventral Blood Islands (aVBI and pVBI) at the different stages in Xenopus laevis embryo. In order to elucidate the regulatory mechanism of myeloid cell differentiation in the aVBI, we examined the role of Nkx2.5, an essential transcription factor for heart differentiation, in regulation of the myeloid cell differentiation in this region. Knockdown of endogenous Nkx2.5 by introducing MO into the dorsal marginal zone (DMZ) suppressed the expression of MHCα as well as that of mpo and spib in the resultant embryos and in DMZ explants made from the injected embryos. Expression of c/ebpα was less affected in the embryos injected with Nkx2.5 MO. The effect of Nkx2.5 MO in myeloid cell differentiation was recovered by coinjection of nkx2.5 or c/ebpα mRNA, indicating that Nkx2.5 functions at the same or the upper level of C/EBPα for the specification of myeloid cells. An attempt to identify transcription factors for myeloid cell differentiation in ventral marginal zone (VMZ) explants demonstrated that coinjection of two transcription factors out of three factors, namely C/EBPα, Nkx2.5 and GATA4, was sufficient to induce a certain amount of mpo expression. We suggest that C/EBPα is an unequivocal factor for myeloid cell differentiation in the aVBI and that Nkx2.5 and GATA4 cooperate with C/EBPα for promotion of myeloid cell differentiation.
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distinct mechanisms control the timing of differentiation of two myeloid populations in xenopus ventral Blood Islands
Development Growth & Differentiation, 2012Co-Authors: Mitsugu Maeno, Kyogo Komiyama, Yoko Matsuzaki, Junichi Hosoya, Sayaka Kurihara, Hiroyuki Sakata, Yumi IzutsuAbstract:Previous study has suggested that distinct populations of myeloid cells exist in the anterior ventral Blood Islands (aVBI) and posterior ventral Blood Islands (pVBI) in Xenopus neurula embryo. However, details for differentiation programs of these two populations have not been elucidated. In the present study, we examined the role of Wnt, vascular endothelial growth factor (VEGF) and fibroblast growth factor signals in the regulation of myeloid cell differentiation in the dorsal marginal zone and ventral marginal zone explants that are the sources of myeloid cells in the aVBI and pVBI. We found that regulation of Wnt activity is essential for the differentiation of myeloid cells in the aVBI but is not required for the differentiation of myeloid cells in the pVBI. Endogenous activity of the VEGF signal is necessary for differentiation of myeloid cells in the pVBI but is not involved in the differentiation of myeloid cells in the aVBI. Overall results reveal that distinct mechanisms are involved in the myeloid, erythroid and endothelial cell differentiation in the aVBI and pVBI.
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two step induction of primitive erythrocytes in xenopus laevis embryos signals from the vegetal endoderm and the overlying ectoderm
The International Journal of Developmental Biology, 2001Co-Authors: M Kikkawa, M Yamazaki, Y Izutsu, Mitsugu MaenoAbstract:Primitive Blood cells differentiate from the ventral mesoderm Blood Islands in Xenopus embryos. In order to determine the tissue interactions that propagate Blood formation in early embryogenesis, we used embryos that had the ventral cytoplasm removed. These embryos gastrulated normally, formed a mesodermal layer and lacked axial structures, but displayed a marked enhancement of alpha-globin expression. Early ventral markers, such as msx-1, vent-1 and vent-2 were highly expressed at the gastrula stage, while a dorsal marker, goosecoid, was diminished. Several lines of experimental evidence demonstrate the critical role of animal pole-derived ectoderm in Blood cell formation: 1) Mesoderm derived from dorsal blastomeres injected with beta-galactosidase mRNA (as a lineage tracer) expressed alpha-globin when interfaced with an animal pole-derived ectodermal layer; 2) Embryos in which the animal pole tissue had been removed by dissection at the blastula stage failed to express alpha-globin; 3) Exogastrulated embryos that lacked an interaction between the mesodermal and ectodermal layers failed to form Blood cells, while muscle cells were observed in these embryos. Using dominant-negative forms of the BMP-4 and ALK-4 receptors, we showed that activin and BMP-4 signaling is necessary for Blood cell differentiation in ventral marginal zone explants, while FGF signaling is not essential. In ventralized embryos, inactivation of the BMP-4 signal within a localized area of the ectoderm led to suppression of globin expression in the adjacent mesoderm layer, but inactivation of the activin signal did not have this effect. These observations suggest that mesodermal cells, derived from a default pathway that is induced by the activin signal, need an additional BMP-4-dependent factor from the overlying ectoderm for further differentiation into a Blood cell lineage.
Philippe Huber - One of the best experts on this subject based on the ideXlab platform.
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role of vascular endothelial cadherin in vascular morphogenesis
Development, 1999Co-Authors: Sylvie Goryfaure, Mariehelene Prandini, Herve Pointu, Valerie Roullot, Isabelle Pignotpaintrand, Muriel Vernet, Philippe HuberAbstract:Vascular endothelial (VE)-cadherin is an adhesive transmembrane protein specifically expressed at interendothelial junctions. Its extracellular domain exhibits Ca2+-dependent homophilic reactivity, promoting cell-cell recognition. Mice deficient in VE-cadherin die at mid-gestation resulting from severe vascular defects. At the early phases of vascular development (E8.5) of VE-cadherin-deficient embryos, in situ differentiation of endothelial cells was delayed although their differentiation program appeared normal. Vascularization was defective in the anterior part of the embryo, while dorsal aortae and vitelline and umbilical arteries formed normally in the caudal part. At E9.25, organization of endothelial cells into large vessels was incomplete and angiogenesis was impaired in mutant embryos. Defects were more severe in extraembryonic vasculature. Blood Islands of the yolk sac and clusters of angioblasts in allantois failed to establish a capillary plexus and remained isolated. This was not due to defective cell-cell recognition as endothelial cells formed intercellular junctions, as shown by electron microscopy. These data indicate that VE-cadherin is dispensable for endothelial homophilic adhesion but is required for vascular morphogenesis.