scholarly journals Polycomb and Notch signaling regulate cell proliferation potential duringCaenorhabditis eleganslife cycle

2018 ◽  
Vol 2 (1) ◽  
pp. e201800170 ◽  
Author(s):  
Francesca Coraggio ◽  
Ringo Püschel ◽  
Alisha Marti ◽  
Peter Meister
Keyword(s):  
Cell Proliferation ◽  
Notch Signaling ◽  
Cell Fate ◽  
Essential Feature ◽  
Wild Type ◽  
H3k27 Methylation ◽  
Histone 3 ◽  
Proliferation And Differentiation ◽  
Multicellular Organisms ◽  
Proliferation Potential

Stable cell fate is an essential feature for multicellular organisms in which individual cells achieve specialized functions.Caenorhabditis elegansis a great model to analyze the determinants of cell fate stability because of its invariant lineage. We present a tractable cell fate challenge system that uses the induction of fate-specifying transcription factors. We show that wild-type differentiated animals are highly resistant to fate challenge. Removal of heterochromatin marks showed marked differences: the absence of histone 3 lysine 9 methylation (H3K9) has no effect on fate stability, whereas Polycomb homologmes-2mutants lacking H3K27 methylation terminally arrest larval development upon fate challenge. Unexpectedly, the arrest correlated with widespread cell proliferation rather than transdifferentiation. Using a candidate RNAi larval arrest-rescue screen, we show that the LIN-12Notchpathway is essential for hyperplasia induction. Moreover, Notch signaling appears downstream of food-sensing pathways, as dauers and first larval stage diapause animals are resistant to fate challenge. Our results demonstrate an equilibrium between proliferation and differentiation regulated by Polycomb and Notch signaling in the soma during the nematode life cycle.

Wingless signaling generates pattern through two distinct mechanisms

Development ◽  
1997 ◽  
Vol 124 (19) ◽  
pp. 3727-3736 ◽  
Author(s):  
R. Hays ◽  
G.B. Gibori ◽  
A. Bejsovec
Keyword(s):  
Cell Fate ◽  
Cellular Response ◽  
Biological Activities ◽  
Essential Feature ◽  
Structural Features ◽  
Protein Distribution ◽  
Wild Type ◽  
Cell Fates ◽  
Amino Acid Region ◽  
Acid Region

wingless (wg) and its vertebrate homologues, the Wnt genes, play critical roles in the generation of embryonic pattern. In the developing Drosophila epidermis, wg is expressed in a single row of cells in each segment, but it influences cell identities in all rows of epidermal cells in the 10- to 12-cell-wide segment. Wg signaling promotes specification of two distinct aspects of the wild-type intrasegmental pattern: the diversity of denticle types present in the anterior denticle belt and the smooth or naked cuticle constituting the posterior surface of the segment. We have manipulated the expression of wild-type and mutant wg transgenes to explore the mechanism by which a single secreted signaling molecule can promote these distinctly different cell fates. We present evidence consistent with the idea that naked cuticle cell fate is specified by a cellular pathway distinct from the denticle diversity-generating pathway. Since these pathways are differentially activated by mutant Wg ligands, we propose that at least two discrete classes of receptor for Wg may exist, each transducing a different cellular response. We also find that broad Wg protein distribution across many cell diameters is required for the generation of denticle diversity, suggesting that intercellular transport of the Wg protein is an essential feature of pattern formation within the epidermal epithelium. Finally, we demonstrate that an 85 amino acid region not conserved in vertebrate Wnts is dispensable for Wg function and we discuss structural features of the Wingless protein required for its distinct biological activities.

scholarly journals Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia

2012 ◽  
Vol 209 (4) ◽  
pp. 713-728 ◽  
Author(s):  
Keunwook Lee ◽  
Ki Taek Nam ◽  
Sung Hoon Cho ◽  
Prathyusha Gudapati ◽  
Yoonha Hwang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
Lymphoblastic Leukemia ◽  
Notch Receptor ◽  
Leukemic Cells ◽  
Cell Fate Decisions ◽  
Proliferation And Differentiation ◽  
Physiological Outcomes

Notch plays critical roles in both cell fate decisions and tumorigenesis. Notch receptor engagement initiates signaling cascades that include a phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway. Mammalian TOR (mTOR) participates in two distinct biochemical complexes, mTORC1 and mTORC2, and the relationship between mTORC2 and physiological outcomes dependent on Notch signaling is unknown. In this study, we report contributions of mTORC2 to thymic T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch. Conditional deletion of Rictor, an essential component of mTORC2, impaired Notch-driven proliferation and differentiation of pre-T cells. Furthermore, NF-κB activity depended on the integrity of mTORC2 in thymocytes. Active Akt restored NF-κB activation, a normal rate of proliferation, and differentiation of Rictor-deficient pre-T cells. Strikingly, mTORC2 depletion lowered CCR7 expression in thymocytes and leukemic cells, accompanied by decreased tissue invasion and delayed mortality in T-ALL driven by Notch. Collectively, these findings reveal roles for mTORC2 in promoting thymic T cell development and T-ALL and indicate that mTORC2 is crucial for Notch signaling to regulate Akt and NF-κB.

scholarly journals Hyperactive WNT/CTNNB1 signaling induces a competing cell proliferation and epidermal differentiation response in the mouse mammary epithelium

2021 ◽  
Author(s):  
Larissa Mourao ◽  
Amber L. Zeeman ◽  
Katrin E. Wiese ◽  
Anika Bongaarts ◽  
Lieve L. Oudejans ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Fate ◽  
De Novo ◽  
Mammary Epithelium ◽  
Mechanistic Explanation ◽  
Tumor Formation ◽  
Epidermal Differentiation ◽  
Cell Proliferation And Differentiation ◽  
Primary Mouse ◽  
Proliferation And Differentiation

In the past forty years, the WNT/CTNNB1 signaling pathway has emerged as a key player in mammary gland development and homeostasis. While also evidently involved in breast cancer, much unclarity continues to surround its precise role in mammary tumor formation and progression. This is largely due to the fact that the specific and direct effects of hyperactive WNT/CTNNB1 signaling on the mammary epithelium remain unknown. Here we use a primary mouse mammary organoid culture system to close this fundamental knowledge gap. We show that hyperactive WNT/CTNNB1 signaling induces competing cell proliferation and differentiation responses. While proliferation is dominant at lower levels of WNT/CTNNB1 signaling activity, higher levels cause reprogramming towards an epidermal cell fate. We show that this involves de novo activation of the epidermal differentiation cluster (EDC) locus and we identify master regulatory transcription factors that likely control the process. This is the first time that the molecular and cellular dose-response effects of WNT/CTNNB1 signaling in the mammary epithelium have been dissected in such detail. Our analyses reveal that the mammary epithelium is exquisitely sensitive to small changes in WNT/CTNNB1 signaling and offer a mechanistic explanation for the squamous differentiation that is observed in some WNT/CTNNB1 driven tumors.

scholarly journals Prognostic Significance ofNOTCH1andFBXW7Mutations in Pediatric T-ALL

2010 ◽  
Vol 28 (6) ◽  
pp. 353-360 ◽  
Author(s):  
Yucel Erbilgin ◽  
Muge Sayitoglu ◽  
Ozden Hatirnaz ◽  
Omer Dogru ◽  
Arzu Akcay ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Notch Signaling ◽  
B Lymphocyte ◽  
Prognostic Significance ◽  
Notch Signaling Pathway ◽  
Biological Data ◽  
Multicellular Organisms ◽  
Relationship Of ◽  
The Relationship

The NOTCH signaling pathway plays important role in the development of multicellular organisms, as it regulates cell proliferation, survival, and differentiation. In adults, it is essential for the T- or B-lymphocyte lineage commitment.NOTCH1and FBXW7 mutations both lead the activation of theNOTCH1pathway and are found in the majority of T-ALL patients. In this study, the mutation analysis ofNOTCH1andFBXW7genes was performed in 87 pediatric T-ALLs who were treated on the ALL-BFM protocols. In 19 patients (22%), activatingNOTCH1mutations were observed either in the heterodimerization domain or in the PEST domain and 7 cases (10%) demonstrated FBXW7 mutations (2 cases had bothNOTCH1andFBXW7mutations). We also analyzed the relationship of the mutation data between the clinical and biological data of the patients.NOTCH1andFBXW7,NOTCH1alone were found correlated with lower initial leucocyte counts which was independent from the sex and T- cell immunophenotype. However,NOTCH1andFBXW7mutations were not predictive of outcome in the overall cohort of pediatric T-ALLs.

scholarly journals JNK1 Induces Notch1 Expression to Regulate Genes Governing Photoreceptor Production

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 970
Author(s):  
Pan ◽  
Hu ◽  
Wang ◽  
Zhou ◽  
Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcriptional Factor ◽  
Negative Regulator ◽  
Potential Candidate ◽  
Wild Type ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Factor Expression ◽  
Ophthalmic Diseases ◽  
Essential Function

c-Jun N-terminal kinases (JNKs) regulate cell proliferation and differentiation via phosphorylating such transcription factors as c-Jun. The function of JNKs in retinogenesis remains to be elucidated. Here, we report that knocking out Jnk1, but not Jnk2, increased the number of photoreceptors, thus enhancing the electroretinogram (ERG) responses. Intriguingly, Notch1, a well-established negative regulator of photoreceptor genesis, was significantly attenuated in Jnk1 knockout (KO) mice compared to wild-type mice. Mechanistically, light specifically activated JNK1 to phosphorylate c-Jun, which in turn induced Notch1 transcription. The identified JNK1–c-Jun–Notch1 axis strongly inhibited photoreceptor-related transcriptional factor expression and ultimately impaired photoreceptor opsin expression. Our study uncovered an essential function of JNK1 in retinogenesis, revealing JNK1 as a potential candidate for targeting ophthalmic diseases.

scholarly journals Notch Signaling in T-Cell Development and T-ALL

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Xiaoyu Li ◽  
Harald von Boehmer
Keyword(s):  
T Cell ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Cell Fate ◽  
Notch Signaling Pathway ◽  
Lineage Specification ◽  
Evolutionarily Conserved ◽  
Multiple Levels ◽  
Multicellular Organisms ◽  
T Cell Maturation

The Notch signaling pathway is an evolutionarily conserved cell signaling system present in most multicellular organisms, as it controls cell fate specification by regulating cell proliferation, differentiation, apoptosis, and survival. Regulation of the Notch signaling pathway can be achieved at multiple levels. Notch proteins are involved in lineage fate decisions in a variety of tissues in various species. Notch is essential for T lineage cell differentiation including T versus B and αβ versus γδ lineage specification. In this paper, we discuss Notch signaling in normal T-cell maturation and differentiation as well as in T-cell acute lymphoblastic lymphoma/leukemia.

scholarly journals Antagonistic roles of Polycomb repression and Notch signaling in the maintenance of somatic cell fate in C. elegans.

2016 ◽  
Author(s):  
Ringo Pueschel ◽  
Francesca Coraggio ◽  
Alisha Marti ◽  
Peter Meister
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Ectopic Expression ◽  
Epigenetic Mark ◽  
Cell Plasticity ◽  
Cell Therapies ◽  
Polycomb Repressive Complex 2 ◽  
C Elegans ◽  
H3k27 Methylation ◽  
Histone H3k27

AbstractReprogramming of somatic cells in intact nematodes allows characterization of cell plasticity determinants, which knowledge is crucial for regenerative cell therapies. By inducing muscle or endoderm transdifferentiation by the ectopic expression of selector transcription factors, we show that cell fate is remarkably robust in fully differentiated larvae. This stability depends on the presence of the Polycomb-associated histone H3K27 methylation, but not H3K9 methylation: in the absence of this epigenetic mark, many cells can be transdifferentiated which correlates with definitive developmental arrest. A candidate RNAi screen unexpectedly uncovered that knock-down of somatic NotchLIN-12 signaling rescues this larval arrest. Similarly in a wild-type context, genetically increasing NotchLIN-12 signaling renders a fraction of the animals sensitive to induced transdifferentiation. This reveals an antagonistic role of the Polycomb repressive complex 2 stabilizing cell fate and Notch signaling enhancing cell plasticity.

Biophysics of Notch Signaling

2021 ◽  
Vol 50 (1) ◽  
Author(s):  
David Sprinzak ◽  
Stephen C. Blacklow
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Annual Review ◽  
Publication Date ◽  
Dynamic Features ◽  
Signaling Mechanism ◽  
Cell Fate Decisions ◽  
Notch Intracellular Domain ◽  
Numerous Cell ◽  
Multicellular Organisms

Notch signaling is a conserved system of communication between adjacent cells, influencing numerous cell fate decisions in the development of multicellular organisms. Aberrant signaling is also implicated in many human pathologies. At its core, Notch has a mechanotransduction module that decodes receptor–ligand engagement at the cell surface under force to permit proteolytic cleavage of the receptor, leading to the release of the Notch intracellular domain (NICD). NICD enters the nucleus and acts as a transcriptional effector to regulate expression of Notch-responsive genes. In this article, we review and integrate current understanding of the detailed molecular basis for Notch signal transduction, highlighting quantitative, structural, and dynamic features of this developmentally central signaling mechanism. We discuss the implications of this mechanistic understanding for the functionality of the signaling pathway in different molecular and cellular contexts. Expected final online publication date for the Annual Review of Biophysics, Volume 50 is May 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Notch Signaling in Mammalian Intestinal Stem Cells: Determining Cell Fate and Maintaining Homeostasis

2019 ◽  
Vol 14 (7) ◽  
pp. 583-590 ◽  
Author(s):  
Shao-jie Liang ◽  
Xiang-guang Li ◽  
Xiu-qi Wang
Keyword(s):  
Stem Cells ◽  
Notch Signaling ◽  
Cell Fate ◽  
Notch Signaling Pathway ◽  
Notch Receptor ◽  
Intestinal Stem Cells ◽  
Research Progress ◽  
Distinct Cell ◽  
Proliferation And Differentiation ◽  
Therapy Strategies

: The intestine serves mainly as a place for digestion and absorption and functions as an immune and endocrine organ. Intestinal stem cells (ISCs) play critical roles in the maintenance of intestinal homeostasis and regeneration, and a complex of signaling pathways is involved in these processes. The Notch signaling pathway is induced via distinct cell-to-cell connections, which are activated through the binding of the Notch ligand on the surface of niche cells to the Notch receptor on ISCs. Numerous studies have shown the central importance of Notch signaling in the proliferation and differentiation of ISCs. Here, we summarize the latest research progress on the crucial functions of Notch signaling in maintaining homeostasis and determining the cell fate of ISCs. Furthermore, the challenges of Notch signaling in colon cancer therapy strategies are also discussed. Several important questions regarding Notch regulation of ISCs are proposed.

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