Notch signalling and the control of cell fate choices in vertebrates

1998 ◽  
Vol 9 (6) ◽  
pp. 583-589 ◽  
Author(s):  
Julian Lewis
Keyword(s):  
Cell Fate ◽  
Notch Signalling

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.

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.

A subset of notch functions during Drosophila eye development require Su(H) and the E(spl) gene complex

Development ◽  
1998 ◽  
Vol 125 (15) ◽  
pp. 2893-2900 ◽  
Author(s):  
P. Ligoxygakis ◽  
S.Y. Yu ◽  
C. Delidakis ◽  
N.E. Baker
Keyword(s):  
Cell Fate ◽  
Notch Pathway ◽  
Signal Transduction Pathway ◽  
Notch Signalling ◽  
Transduction Pathway ◽  
Notch Signalling Pathway ◽  
Bhlh Genes ◽  
Drosophila Eye ◽  
Enhancer Of Split ◽  
Signalling Process

The Notch signalling pathway is involved in many processes where cell fate is decided. Previous work showed that Notch is required at successive steps during R8 specification in the Drosophila eye. Initially, Notch enhances atonal expression and promotes atonal function. After atonal autoregulation has been established, Notch signalling represses atonal expression during lateral specification. In this paper we investigate which known components of the Notch pathway are involved in each signalling process. Using clonal analysis we show that a ligand of Notch, Delta, is required along with Notch for both proneural enhancement and lateral specification, while the downstream components Suppressor-of-Hairless and Enhancer-of-Split are involved only in lateral specification. Our data point to a distinct signal transduction pathway during proneural enhancement by Notch. Using misexpression experiments we also show that particular Enhancer-of-split bHLH genes can differ greatly in their contribution to lateral specification.

scholarly journals Cell and molecular biology of Notch

2007 ◽  
Vol 194 (3) ◽  
pp. 459-474 ◽  
Author(s):  
Ulla-Maj Fiúza ◽  
Alfonso Martinez Arias
Keyword(s):  
Cell Fate ◽  
Cell Communication ◽  
Notch Signalling ◽  
Multiple Roles ◽  
Communication Process ◽  
Regulatory Mechanisms ◽  
Cell Populations ◽  
Notch Signalling Pathway ◽  
A Cell ◽  
Stem Cell Populations

Notch signalling is a cell–cell communication process, which allows the establishment of patterns of gene expression and differentiation, regulates binary cell fate choice and the maintenance of stem cell populations. So far, the data published has elucidated the main players in the Notch signalling pathway. However, its regulatory mechanisms are exhibiting an increasing complexity which could account for the multitude of roles it has during development and in adult organisms. In this review, we will describe the multiple roles of Notch and how various factors can regulate Notch signalling.

scholarly journals Mib-Jag1-Notch signalling regulates patterning and structural roles of the notochord by controlling cell-fate decisions

Development ◽  
2010 ◽  
Vol 137 (15) ◽  
pp. 2527-2537 ◽  
Author(s):  
M. Yamamoto ◽  
R. Morita ◽  
T. Mizoguchi ◽  
H. Matsuo ◽  
M. Isoda ◽  
...  
Keyword(s):  
Cell Fate ◽  
Notch Signalling ◽  
Cell Fate Decisions

scholarly journals Mitochondria define intestinal stem cell differentiation downstream of a FOXO/Notch axis

2019 ◽  
Author(s):  
M.C. Ludikhuize ◽  
M. Meerlo ◽  
M. Pages Gallego ◽  
M. Burgaya Julià ◽  
N.T.B. Nguyen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Cell Fate ◽  
Cell Function ◽  
Mitochondrial Fission ◽  
Stem Cell Differentiation ◽  
Notch Signalling ◽  
Intestinal Stem Cell ◽  
Mitochondrial Activity ◽  
Foxo Transcription Factors

SummaryDifferential signalling of the WNT and Notch pathways regulates proliferation and differentiation of Lgr5+ crypt-based columnar cells (CBCs) into all cell lineages of the intestine. We have recently shown that high mitochondrial activity in CBCs is key in maintaining stem cell function. Interestingly, while high mitochondrial activity drives CBCs, it is reduced in the adjacent secretory Paneth cells (PCs). This observation implies that during differentiation towards PCs, CBCs undergo a metabolic rewiring involving downregulation of mitochondrial number and activity, through a hitherto unknown mechanism. Here we demonstrate, using intestinal organoids that FoxO transcription factors and Notch signalling functionally interact in determining CBC cell fate. In agreement with the organoid data, combined Foxo1 and 3 deletion in mice increases PC number in the intestine. Importantly, we show that FOXO and Notch signalling converge onto regulation of mitochondrial fission, which in turn provokes stem cell differentiation into the secretory types; Goblet cells and PCs. Finally, mapping intestinal stem cell differentiation based on pseudotime computation of scRNA-seq data further supports the role of FOXO, Notch and mitochondria in determining secretory differentiation. This shows that mitochondria is not only a discriminatory hallmark of CBCs and PCs, but that its status actively determines lineage commitment during differentiation. Together, our work describes a new signalling-metabolic axis in stem cell differentiation and highlights the importance of mitochondria in determining cell fate.

scholarly journals The transcription factor LAG-1/CSL plays a Notch-independent role in controlling terminal differentiation, fate maintenance, and plasticity of serotonergic chemosensory neurons

PLoS Biology ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. e3001334
Author(s):  
Miren Maicas ◽  
Ángela Jimeno-Martín ◽  
Andrea Millán-Trejo ◽  
Mark J. Alkema ◽  
Nuria Flames
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Genes ◽  
Cell Signalling ◽  
Notch Pathway ◽  
Receptor Activation ◽  
Notch Signalling ◽  
Notch Receptor ◽  
Specific Gene ◽  
Effector Genes

During development, signal-regulated transcription factors (TFs) act as basal repressors and upon signalling through morphogens or cell-to-cell signalling shift to activators, mediating precise and transient responses. Conversely, at the final steps of neuron specification, terminal selector TFs directly initiate and maintain neuron-type specific gene expression through enduring functions as activators. C. elegans contains 3 types of serotonin synthesising neurons that share the expression of the serotonin biosynthesis pathway genes but not of other effector genes. Here, we find an unconventional role for LAG-1, the signal-regulated TF mediator of the Notch pathway, as terminal selector for the ADF serotonergic chemosensory neuron, but not for other serotonergic neuron types. Regulatory regions of ADF effector genes contain functional LAG-1 binding sites that mediate activation but not basal repression. lag-1 mutants show broad defects in ADF effector genes activation, and LAG-1 is required to maintain ADF cell fate and functions throughout life. Unexpectedly, contrary to reported basal repression state for LAG-1 prior to Notch receptor activation, gene expression activation in the ADF neuron by LAG-1 does not require Notch signalling, demonstrating a default activator state for LAG-1 independent of Notch. We hypothesise that the enduring activity of terminal selectors on target genes required uncoupling LAG-1 activating role from receiving the transient Notch signalling.

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