neuralized is essential for a subset of Notch pathway-dependent cell fate decisions during Drosophila eye development

The Notch signaling pathway is a versatile regulator of cell fate decisions and plays an essential role for embryonic and postnatal vascular development. As only modest differences in Notch pathway activity suffice to determine dramatic differences in blood vessel development, this pathway is tightly regulated by a variety of molecular mechanisms. Reversible acetylation has emerged as an important post-translational modification of several non-histone proteins, which are targeted by histone deacetylases (HDACs). Here, we report that specifically the Notch1 intracellular domain (NICD) is itself an acetylated protein and that its acetylation level is tightly regulated by the SIRT1 deacetylase, which we have previously identified as a key regulator of endothelial angiogenic functions during vascular growth. Coexpression of NICD with histone acetyltransferases such as p300 or PCAF induced a dose- and time-dependent acetylation of NICD. Blocking HDAC activity using the class III HDAC inhibitor nicotinamid (NAM), but not the class I/II HDAC inhibior trichostatin A, resulted in a significant increase of NICD acetylation suggesting that NICD is targetd by class III HDACs for deacetylation. Among the class III HDACs with deacetylase activity (SIRT1, 2, 3, 5), knock down of specifically SIRT1 resulted in enhanced acetylation of NICD. Moreover, wild type SIRT1, but not a catalytically inactive mutant catalyzed the deacetylation of NICD in a nicotinamid-dependent manner. SIRT1, but SIRT2, SIRT3 or SIRT5, associated with NICD through its catalytic domain demonstrating that SIRT1 is a direct NICD deacetylase. Enhancing NICD acetylation by either overexpression of p300 or inhibition of SIRT1 activity using NAM or RNAi-mediated knock down resulted in enhanced NICD protein stability by blocking its ubiquitin-mediated degradation. Consistent with these results, loss of SIRT1 amplified Notch target gene expression in endothelial cells in response to NICD overexpression or treatment with the Notch ligand Dll4. In summary, our results identify reversible acetylation of NICD as a novel molecular mechanism to control Notch signaling and suggest that deacetylation of NICD by SIRT1 plays a key role in the dynamic regulation of Notch signaling in endothelial cells.

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Role of Notch and achaete-scute complex in the expression of Enhancer of split bHLH proteins

Development ◽

10.1242/dev.121.11.3745 ◽

1995 ◽

Vol 121 (11) ◽

pp. 3745-3752 ◽

Cited By ~ 13

Author(s):

V. Jennings ◽

J. de Celis ◽

C. Delidakis ◽

A. Preiss ◽

S. Bray

Keyword(s):

Cell Fate ◽

Notch Pathway ◽

Interaction Mechanism ◽

Cell Interaction ◽

Precursor Cell ◽

Notch Receptor ◽

Sensory Organ ◽

Cell Fate Decisions ◽

Sensory Organ Precursor ◽

Enhancer Of Split

The proteins encoded by Notch and the Enhancer of split complex are components of a cell-cell interaction mechanism which is important in many cell fate decisions throughout development. One such decision is the formation of the sensory organ precursor cell during the development of the peripheral nervous system in Drosophila. Cells acquire the potential to be neural through the expression of the proneural genes, and the Notch pathway is required to limit neural fate to a single cell from a proneural cluster. However, despite extensive analysis, the precise pathways linking the proneural with Notch and Enhancer of split gene functions remain obscure. For example, it has been suggested that achaete-scute complex proteins directly activate Enhancer of split genes leaving the action of Notch in the pathway unclear. Using monoclonal antibodies that recognise products of the Enhancer of split complex, we show that these proteins accumulate in the cells surrounding the developing sensory organ precursor cell and that their expression is dependent on the activity of Notch and does not directly correlate with expression of Achaete. We further clarify the pathway by showing that ubiquitous expression of an activated Notch receptor leads to widespread accumulation of Enhancer of split proteins even in the absence of achaete-scute complex proteins. Thus Enhancer of split protein expression in response to Notch activity does not require achaete-scute complex proteins.

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Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis

Development ◽

10.1242/dev.127.17.3865 ◽

2000 ◽

Vol 127 (17) ◽

pp. 3865-3876

Author(s):

M.S. Rones ◽

K.A. McLaughlin ◽

M. Raffin ◽

M. Mercola

Keyword(s):

Gene Expression ◽

Notch Signaling ◽

Cell Fate ◽

Notch Pathway ◽

Cell Types ◽

Myocardial Cell ◽

Dominant Negative ◽

Cell Fates ◽

Cell Fate Decisions ◽

Heart Field

Notch signaling mediates numerous developmental cell fate decisions in organisms ranging from flies to humans, resulting in the generation of multiple cell types from equipotential precursors. In this paper, we present evidence that activation of Notch by its ligand Serrate apportions myogenic and non-myogenic cell fates within the early Xenopus heart field. The crescent-shaped field of heart mesoderm is specified initially as cardiomyogenic. While the ventral region of the field forms the myocardial tube, the dorsolateral portions lose myogenic potency and form the dorsal mesocardium and pericardial roof (Raffin, M., Leong, L. M., Rones, M. S., Sparrow, D., Mohun, T. and Mercola, M. (2000) Dev. Biol., 218, 326–340). The local interactions that establish or maintain the distinct myocardial and non-myocardial domains have never been described. Here we show that Xenopus Notch1 (Xotch) and Serrate1 are expressed in overlapping patterns in the early heart field. Conditional activation or inhibition of the Notch pathway with inducible dominant negative or active forms of the RBP-J/Suppressor of Hairless [Su(H)] transcription factor indicated that activation of Notch feeds back on Serrate1 gene expression to localize transcripts more dorsolaterally than those of Notch1, with overlap in the region of the developing mesocardium. Moreover, Notch pathway activation decreased myocardial gene expression and increased expression of a marker of the mesocardium and pericardial roof, whereas inhibition of Notch signaling had the opposite effect. Activation or inhibition of Notch also regulated contribution of individual cells to the myocardium. Importantly, expression of Nkx2. 5 and Gata4 remained largely unaffected, indicating that Notch signaling functions downstream of heart field specification. We conclude that Notch signaling through Su(H) suppresses cardiomyogenesis and that this activity is essential for the correct specification of myocardial and non-myocardial cell fates.

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Conservation of the Notch signalling pathway in mammalian neurogenesis

Development ◽

10.1242/dev.124.6.1139 ◽

1997 ◽

Vol 124 (6) ◽

pp. 1139-1148 ◽

Cited By ~ 31

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.

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Cancer Stem Cells, Quo Vadis? The Notch Signaling Pathway in Tumor Initiation and Progression

Cells ◽

10.3390/cells9081879 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1879 ◽

Cited By ~ 2

Author(s):

Christian T. Meisel ◽

Cristina Porcheri ◽

Thimios A. Mitsiadis

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Notch Signaling ◽

Signaling Pathway ◽

Cell Fate ◽

Adult Life ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Fine Tuning ◽

Cell Fate Decisions

The Notch signaling pathway regulates cell proliferation, cytodifferentiation and cell fate decisions in both embryonic and adult life. Several aspects of stem cell maintenance are dependent from the functionality and fine tuning of the Notch pathway. In cancer, Notch is specifically involved in preserving self-renewal and amplification of cancer stem cells, supporting the formation, spread and recurrence of the tumor. As the function of Notch signaling is context dependent, we here provide an overview of its activity in a variety of tumors, focusing mostly on its role in the maintenance of the undifferentiated subset of cancer cells. Finally, we analyze the potential of molecules of the Notch pathway as diagnostic and therapeutic tools against the various cancers.

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The Notch pathway regulates both the proliferation and differentiation of follicular cells in the panoistic ovary of Blattella germanica

Open Biology ◽

10.1098/rsob.150197 ◽

2016 ◽

Vol 6 (1) ◽

pp. 150197 ◽

Cited By ~ 11

Author(s):

Paula Irles ◽

Nashwa Elshaer ◽

Maria-Dolors Piulachs

Keyword(s):

Cell Fate ◽

Ovarian Follicle ◽

Notch Pathway ◽

Blattella Germanica ◽

Active Role ◽

Follicular Cells ◽

Cell Fate Decisions ◽

Proliferation And Differentiation ◽

Ancestral Function ◽

Main Components

The Notch pathway is an essential regulator of cell proliferation and differentiation during development. Its involvement in insect oogenesis has been examined in insect species with meroistic ovaries, and it is known to play a fundamental role in cell fate decisions and the induction of the mitosis-to-endocycle switch in follicular cells (FCs). This work reports the functions of the main components of the Notch pathway (Notch and its ligands Delta and Serrate) during oogenesis in Blattella germanica , a phylogenetically basal species with panoistic ovary. As is revealed by RNAi-based analyses, Notch and Delta were found to contribute towards maintaining the FCs in an immature, non-apoptotic state. This ancestral function of Notch appears in opposition to the induction of transition from mitosis to endocycle that Notch exerts in Drosophila melanogaster, a change in the Notch function that might be in agreement with the evolution of the insect ovary types. Notch was also shown to play an active role in inducing ovarian follicle elongation via the regulation of the cytoskeleton. In addition, Delta and Notch interactions were seen to determine the differentiation of the posterior population of FCs. Serrate levels were found to be Notch-dependent and are involved in the control of the FC programme, although they would appear to play no crucial role in panoistic ovary oogenesis.

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Asymmetric Localization of Frizzled and the Determination of Notch-Dependent Cell Fate in the Drosophila Eye

Current Biology ◽

10.1016/s0960-9822(02)00841-2 ◽

2002 ◽

Vol 12 (10) ◽

pp. 813-824 ◽

Cited By ~ 88

Author(s):

David Strutt ◽

Ruth Johnson ◽

Katherine Cooper ◽

Sarah Bray

Keyword(s):

Cell Fate ◽

Drosophila Eye ◽

Dependent Cell

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The Notch Pathway: Modulation of Cell Fate Decisions in Hematopoiesis

International Journal of Hematology ◽

10.1007/bf02982106 ◽

2002 ◽

Vol 75 (5) ◽

pp. 449-459 ◽

Cited By ~ 43

Author(s):

K. Ohishi ◽

B. Varnum-Finney ◽

I. D. Bernstein

Keyword(s):

Cell Fate ◽

Notch Pathway ◽

Cell Fate Decisions

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hecd-1 Modulates Notch Activity in Caenorhabditis elegans

G3 Genes|Genome|Genetics ◽

10.1534/g3.114.015321 ◽

2015 ◽

Vol 5 (3) ◽

pp. 353-359 ◽

Cited By ~ 3

Author(s):

Yunting Chen ◽

Iva Greenwald

Keyword(s):

Quality Control ◽

Caenorhabditis Elegans ◽

Cell Fate ◽

Germ Line ◽

Notch Pathway ◽

Cell Fate Decisions ◽

Notch Activity ◽

C Elegans ◽

Somatic Gonad ◽

Constitutively Active

Abstract Notch is a receptor that mediates cell–cell interactions that specify binary cell fate decisions in development and tissue homeostasis. Inappropriate Notch signaling is associated with cancer, and mutations in Notch pathway components have been associated with developmental diseases and syndromes. In Caenorhabditis elegans, suppressors of phenotypes associated with constitutively active LIN-12/Notch have identified many conserved core components and direct or indirect modulators. Here, we molecularly identify sel(ar584), originally isolated as a suppressor of a constitutively active allele of lin-12. We show that sel(ar584) is an allele of hecd-1, the ortholog of human HECDT1, a ubiquitin ligase that has been implicated in several different mammalian developmental events. We studied interactions of hecd-1 with lin-12 in the somatic gonad and with the other C. elegans Notch gene, glp-1, in the germ line. We found that hecd-1 acts as a positive modulator of lin-12/Notch activity in a somatic gonad context—the original basis for its isolation—but acts autonomously as a negative modulator of glp-1/Notch activity in the germ line. As the yeast ortholog of HECD-1, Ufd4p, has been shown to function in quality control, and C. elegans HECD-1 has been shown to affect mitochondrial maintenance, we propose that the different genetic interactions between hecd-1 and Notch genes we observed in different cell contexts may reflect differences in quality control regulatory mechanisms or in cellular metabolism.

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