scholarly journals Erratum: Corrigendum: Regulation of monocyte cell fate by blood vessels mediated by Notch signalling

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Jaba Gamrekelashvili ◽  
Roberto Giagnorio ◽  
Jasmin Jussofie ◽  
Oliver Soehnlein ◽  
Johan Duchene ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Cell Fate ◽  
Notch Signalling ◽  
Monocyte Cell

scholarly journals Regulation of monocyte cell fate by blood vessels mediated by Notch signalling

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Jaba Gamrekelashvili ◽  
Roberto Giagnorio ◽  
Jasmin Jussofie ◽  
Oliver Soehnlein ◽  
Johan Duchene ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Cell Fate ◽  
Myeloid Cell ◽  
Notch Signalling ◽  
Monocyte Cell ◽  
Genetic Deletion ◽  
Cell Fate Tracking

Abstract A population of monocytes, known as Ly6Clo monocytes, patrol blood vessels by crawling along the vascular endothelium. Here we show that endothelial cells control their origin through Notch signalling. Using combinations of conditional genetic deletion strategies and cell-fate tracking experiments we show that Notch2 regulates conversion of Ly6Chi monocytes into Ly6Clo monocytes in vivo and in vitro, thereby regulating monocyte cell fate under steady-state conditions. This process is controlled by Notch ligand delta-like 1 (Dll1) expressed by a population of endothelial cells that constitute distinct vascular niches in the bone marrow and spleen in vivo, while culture on recombinant DLL1 induces monocyte conversion in vitro. Thus, blood vessels regulate monocyte conversion, a form of committed myeloid cell fate regulation.

scholarly journals Coronary blood vessels from distinct origins converge to equivalent states during mouse and human development

2021 ◽  
Author(s):  
Ragini S Phansalkar ◽  
Josephine Krieger ◽  
Mingming Zhao ◽  
Sai Saroja Kolluru ◽  
Robert C Jones ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Cell Fate ◽  
Adult Mouse ◽  
Coronary Vessels ◽  
Lineage Tracing ◽  
Specific Gene ◽  
Cell Type ◽  
Functional Differences ◽  
Coronary Blood Vessels ◽  
Two Populations

Most cell fate trajectories during development follow a diverging, tree-like branching pattern, but the opposite can occur when distinct progenitors contribute to the same cell type. During this convergent differentiation, it is unknown if cells "remember" their origins transcriptionally or whether this influences cell behavior. Most coronary blood vessels of the heart develop from two different progenitor sources-the endocardium (Endo) and sinus venosus (SV)-but whether transcriptional or functional differences related to origin are retained is unknown. We addressed this by combining lineage tracing with single-cell RNA sequencing (scRNAseq) in embryonic and adult mouse hearts. Shortly after coronary development begins, capillary ECs transcriptionally segregated into two states that retained progenitor-specific gene expression. Later in development, when the coronary vasculature is well-established but still remodeling, capillary ECs again segregated into two populations, but transcriptional differences were related to tissue localization rather than lineage. Specifically, ECs in the heart septum expressed genes indicative of increased local hypoxia and decreased blood flow. Adult capillary ECs were more homogeneous and lacked indications of either lineage or location. In agreement, SV- and Endo-derived ECs in adult hearts displayed similar responses to injury. Finally, scRNAseq of developing human coronary vessels indicated that the human heart followed similar principles. Thus, over the course of development, transcriptional heterogeneity in coronary ECs is first influenced by lineage, then by location, until heterogeneity disappears in the homeostatic adult heart. These results highlight the plasticity of ECs during development, and the validity of the mouse as a model for human coronary development.

scholarly journals Notch receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Thiruma V. Arumugam ◽  
Christopher Sobey
Keyword(s):  
Cell Fate ◽  
Single Agent ◽  
Notch Signalling ◽  
Type I ◽  
Notch Receptors ◽  
Anti Cancer ◽  
Close Proximity ◽  
Ligand Interactions ◽  
Transcriptional Modulation ◽  
Membrane Bound

The canonical Notch signalling pathway has four type I transmembrane Notch receptors (Notch1-4) and five ligands (DLL1, 2 and 3, and Jagged 1-2). Each member of this highly conserved receptor family plays a unique role in cell-fate determination during embryogenesis, differentiation, tissue patterning, proliferation and cell death [2]. As the Notch ligands are also membrane bound, cells have to be in close proximity for receptor-ligand interactions to occur. Cleavage of the intracellular domain (ICD) of activated Notch receptors by γ-secretase is required for downstream signalling and Notch-induced transcriptional modulation [15, 3, 11, 22]. This is why γ-secretase inhibitors can be used to downregulate Notch signalling and explains their anti-cancer action. One such small molecule is RO4929097 [8], although development of this compound has been terminated following an unsuccessful Phase II single agent clinical trial in metastatic colorectal cancer [19].Aberrant Notch signalling is implicated in a number of human cancers [12, 20, 6, 16], with demcizumab and tarextumab identified as antibody inhibitors of ligand:receptor binding [13].

Feedback regulation is central to Delta-Notch signalling required for Drosophila wing vein morphogenesis

Development ◽  
1997 ◽  
Vol 124 (17) ◽  
pp. 3283-3291 ◽  
Author(s):  
S.S. Huppert ◽  
T.L. Jacobsen ◽  
M.A. Muskavitch
Keyword(s):  
Protein Expression ◽  
Cell Fate ◽  
Expression Patterns ◽  
Feedback Regulation ◽  
Notch Signalling ◽  
Notch Receptor ◽  
Cell Fates ◽  
Wing Vein ◽  
Drosophila Wing ◽  
Puparium Formation

Delta and Notch are required for partitioning of vein and intervein cell fates within the provein during Drosophila metamorphosis. We find that partitioning of these fates is dependent on Delta-mediated signalling from 22 to 30 hours after puparium formation at 25 degrees C. Within the provein, Delta is expressed more highly in central provein cells (presumptive vein cells) and Notch is expressed more highly in lateral provein cells (presumptive intervein cells). Accumulation of Notch in presumptive intervein cells is dependent on Delta signalling activity in presumptive vein cells and constitutive Notch receptor activity represses Delta accumulation in presumptive vein cells. When Delta protein expression is elevated ectopically in presumptive intervein cells, complementary Delta and Notch expression patterns in provein cells are reversed, and vein loss occurs because central provein cells are unable to stably adopt the vein cell fate. Our findings imply that Delta-Notch signalling exerts feedback regulation on Delta and Notch expression during metamorphic wing vein development, and that the resultant asymmetries in Delta and Notch expression underlie the proper specification of vein and intervein cell fates within the provein.

Conservation of the Notch signalling pathway in mammalian neurogenesis

Development ◽  
1997 ◽  
Vol 124 (6) ◽  
pp. 1139-1148 ◽  
Author(s):  
J.L. Pompa de la ◽  
A. Wakeham ◽  
K.M. Correia ◽  
E. Samper ◽  
S. Brown ◽  
...  
Keyword(s):  
Cell Fate ◽  
Notch Pathway ◽  
Stem Cell Differentiation ◽  
Notch Signalling ◽  
Signalling Pathway ◽  
Notch Signalling Pathway ◽  
Altered Expression ◽  
Cell Fate Decisions ◽  
Targeted Mutation ◽  
Multiple Cell

The Notch pathway functions in multiple cell fate determination processes in invertebrate embryos, including the decision between the neuroblast and epidermoblast lineages in Drosophila. In the mouse, targeted mutation of the Notch pathway genes Notch1 and RBP-Jk has demonstrated a role for these genes in somite segmentation, but a function in neurogenesis and in cell fate decisions has not been shown. Here we show that these mutations lead to altered expression of the Notch signalling pathway homologues Hes-5, Mash-1 and Dll1, resulting in enhanced neurogenesis. Precocious neuronal differentiation is indicated by the expanded expression domains of Math4A, neuroD and NSCL-1. The RBP-Jk mutation has stronger effects on expression of these genes than does the Notch1 mutation, consistent with functional redundancy of Notch genes in neurogenesis. Our results demonstrate conservation of the Notch pathway and its regulatory mechanisms from fly to mouse, and support a role for the murine Notch signalling pathway in the regulation of neural stem cell differentiation.

The Duration of Erk1/2 Signaling Determines Neutrophil Versus Monocyte Cell Fates in Response to G-CSF and M-CSF

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4353-4353
Author(s):  
Nan Hu ◽  
Yaling Qiu ◽  
Fan Dong
Keyword(s):  
Signaling Pathways ◽  
Cell Fate ◽  
Intracellular Signaling ◽  
Strong Support ◽  
Lineage Commitment ◽  
Monocytic Differentiation ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Monocyte Cell ◽  
Neutrophil Cell

Abstract Neutrophils and monocytes/macrophages are derived from hematopoietic stem cells that, through progressive commitment, give rise to granulocyte-monocyte progenitors that in turn develop into either neutrophils or monocytes/macrophages. Although it is well known that cell fate specification in the hematopoietic system depends on the expression of lineage specific transcription factors, the roles of cytokines in lineage commitment are less clear and two models have been proposed. According to the stochastic model, cell fate choice is stochastic and cytokines simply provide signals for the survival and proliferation of committed cells. The instructive model, on the other hand, proposes that cytokines stimulate intracellular signaling pathways that dictate cell fate decisions. G-CSF and M-CSF are two lineage-specific cytokines that play a dominant role in granulopoiesis and monopoiesis, respectively. Recent studies lend strong support to the roles of G-CSF and M-CSF in instructing lineage commitment. However, the signaling pathways that determine neutrophil versus monocyte cell fate following stimulation with G-CSF and M-CSF are unknown. Here we show that tyrosine (Y) 729 of the G-CSFR is involved in transducing signals that specify neutrophil cell fate. Substitution of Y729 with phenylalanine (F) results in monocytic differentiation in response to G-CSF in murine myeloid 32D and multipotent FDCP-mix A4 cells. G-CSF stimulated activation of Erk1/2 was prolonged in cells expressing G-CSFR Y729F mutant. Significantly, treatment of cells with Mek1/2 inhibitors U0126 or PD0325901 rescued neutrophilic differentiation. M-CSF has been shown to induce prolonged activation of Erk1/2, which is required for monocytic differentiation. Interestingly, the Mek1/2 inhibitors also promoted neutrophil cell fate at the expense of monocytic development in lineage marker negative (Lin-) primary bone marrow cells cultured in M-CSF. We further demonstrate that prolonged activation of Erk1/2 was associated with augmented activation of c-Fos and Egr1, both of which have previously been shown to promote monocytic development. Consistent with this, knockdown of c-Fos or Egr1 redirected 32D cells expressing G-CSFR Y729F mutant to develop into neutrophils in response to G-CSF. We propose that M-CSF stimulates more sustained activation of Erk1/2 than G-CSF does and that the duration of Erk1/2 signaling regulates neutrophil versus monocyte cell fate choices, likely through altering the activation statuses of c-Fos and Egr1. Disclosures No relevant conflicts of interest to declare.

Dynamics of Notch signalling in the mouse oviduct and uterus during the oestrous cycle

2016 ◽  
Vol 28 (11) ◽  
pp. 1663 ◽  
Author(s):  
D. Murta ◽  
M. Batista ◽  
A. Trindade ◽  
E. Silva ◽  
L. Mateus ◽  
...  
Keyword(s):  
Real Time ◽  
Cell Fate ◽  
Expression Patterns ◽  
Cell Signalling ◽  
Notch Signalling ◽  
Notch Receptor ◽  
Effector Proteins ◽  
Oestrous Cycle ◽  
Cell Fate Decisions ◽  
Effector Genes

The oviduct and uterus undergo extensive cellular remodelling during the oestrous cycle, requiring finely tuned intercellular communication. Notch is an evolutionarily conserved cell signalling pathway implicated in cell fate decisions in several tissues. In the present study we evaluated the quantitative real-time polymerase chain reaction (real-time qPCR) and expression (immunohistochemistry) patterns of Notch components (Notch1–4, Delta-like 1 (Dll1), Delta-like 4 (Dll4), Jagged1–2) and effector (hairy/enhancer of split (Hes) 1–2, Hes5 and Notch-Regulated Ankyrin Repeat-Containing Protein (Nrarp)) genes in the mouse oviduct and uterus throughout the oestrous cycle. Notch genes are differentially transcribed and expressed in the mouse oviduct and uterus throughout the oestrous cycle. The correlated transcription levels of Notch components and effector genes, and the nuclear detection of Notch effector proteins, indicate that Notch signalling is active. The correlation between transcription levels of Notch genes and progesterone concentrations, and the association between expression of Notch proteins and progesterone receptor (PR) activation, indicate direct progesterone regulation of Notch signalling. The expression patterns of Notch proteins are spatially and temporally specific, resulting in unique expression combinations of Notch receptor, ligand and effector genes in the oviduct luminal epithelium, uterus luminal and glandular epithelia and uterine stroma throughout the oestrous cycle. Together, the results of the present study imply a regulatory role for Notch signalling in oviduct and uterine cellular remodelling occurring throughout the oestrous cycle.

scholarly journals Author response: Notch and TLR signaling coordinate monocyte cell fate and inflammation

2020 ◽  
Author(s):  
Jaba Gamrekelashvili ◽  
Tamar Kapanadze ◽  
Stefan Sablotny ◽  
Corina Ratiu ◽  
Khaled Dastagir ◽  
...  
Keyword(s):  
Cell Fate ◽  
Author Response ◽  
Tlr Signaling ◽  
Monocyte Cell

Notch signaling is required for arterial-venous differentiation during embryonic vascular development

Development ◽  
2001 ◽  
Vol 128 (19) ◽  
pp. 3675-3683 ◽  
Author(s):  
Nathan D. Lawson ◽  
Nico Scheer ◽  
Van N. Pham ◽  
Cheol-Hee Kim ◽  
Ajay B. Chitnis ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Blood Vessels ◽  
Cell Fate ◽  
Venous Blood ◽  
Vascular Development ◽  
Ectopic Expression ◽  
Specific Expression ◽  
Ectopic Activation ◽  
On Line ◽  
Embryonic Vascular Development

Recent evidence indicates that acquisition of artery or vein identity during vascular development is governed, in part, by genetic mechanisms. The artery-specific expression of a number of Notch signaling genes in mouse and zebrafish suggests that this pathway may play a role in arterial-venous cell fate determination during vascular development. We show that loss of Notch signaling in zebrafish embryos leads to molecular defects in arterial-venous differentiation, including loss of artery-specific markers and ectopic expression of venous markers within the dorsal aorta. Conversely, we find that ectopic activation of Notch signaling leads to repression of venous cell fate. Finally, embryos lacking Notch function exhibit defects in blood vessel formation similar to those associated with improper arterial-venous specification. Our results suggest that Notch signaling is required for the proper development of arterial and venous blood vessels, and that a major role of Notch signaling in blood vessels is to repress venous differentiation within developing arteries.Movies available on-line

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