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.

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 Structural and functional studies of the RBPJ-SHARP complex reveal conserved corepressor binding site

2018 ◽  
Author(s):  
Zhenyu Yuan ◽  
Bradley D. VanderWielen ◽  
Benedetto Daniele Giaimo ◽  
Leiling Pan ◽  
Courtney E. Collins ◽  
...  
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Notch Pathway ◽  
Binding Pocket ◽  
Therapeutic Benefit ◽  
Notch Receptor ◽  
Signaling Mechanism ◽  
Cell Fate Decisions ◽  
Functional Studies

AbstractThe Notch pathway is a conserved signaling mechanism that is essential for cell fate decisions during pre and postnatal development. Dysregulated signaling underlies the pathophysiology of numerous human diseases, most notably T-cell acute lymphoblastic leukemia. Receptor-ligand interactions result in changes in gene expression, which are regulated by the transcription factor CSL. CSL forms a complex with the intracellular domain of the Notch receptor and the transcriptional coactivator Mastermind, which is required to activate transcription of all Notch target genes. CSL can also function as repressor by interacting with corepressor proteins, e.g. SHARP in mammals and Hairless in Drosophila melanogaster; however, its role as a transcriptional repressor is not well understood. Here we determine the high-resolution structure of RBPJ, the mouse CSL ortholog, bound to the corepressor SHARP and DNA, which reveals a new mode of corepressor binding to CSL and an interesting example for how ligand binding sites evolve in proteins. Based on the structure, we designed and tested a number of mutants in biophysical, biochemical, and cellular assays to characterize the role of RBPJ as a repressor of Notch target genes. Our cellular studies clearly demonstrate that RBPJ mutants that are deficient for binding SHARP are incapable of repressing transcription from genes responsive to Notch signaling. Altogether, our structure-function studies of the RBPJ-SHARP corepressor complex bound to DNA provide significant insights into the repressor function of RBPJ and identify a new binding pocket on RBPJ that could be targeted for therapeutic benefit.

SUMOylated Non-canonical Polycomb PRC1.6 Complex as a Prerequisite for Recruitment of Transcription Factor RBPJ

2021 ◽  
Author(s):  
Małgorzata Sotomska ◽  
Robert Liefke ◽  
Francesca Ferrante ◽  
Heiko Schwederski ◽  
Franz Oswald ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Fate ◽  
Target Gene ◽  
Target Genes ◽  
Adult Stem Cell ◽  
Notch Signalling ◽  
Cell Fate Decisions ◽  
Contact Points ◽  
Coactivator Complex

Abstract BackgroundNotch signaling controls cell fate decisions in many contexts during development and adult stem cell homeostasis and, when dysregulated, leads to carcinogenesis. The central transcription factor RBPJ assembles the Notch coactivator complex in the presence of Notch signalling, and represses Notch target gene expression in its absence.ResultsWe identified L3MBTL2 and additional members of the non-canonical polycomb repressive PRC1.6 complex in DNA-bound RBPJ associated complexes and demonstrate that L3MBTL2 directly interacts with RBPJ. Depletion of RBPJ does not affect occupancy of PRC1.6 components at Notch target genes. Conversely, absence of L3MBTL2 reduces RBPJ occupancy at enhancers of Notch target genes. Since L3MBTL2 and additional members of the PRC1.6 are known to be SUMOylated, we investigated whether RBPJ uses SUMO-moieties as contact points. Indeed, we found that RBPJ binds to SUMO2/3 and that this interaction depends on a defined SUMO-interaction motif. Furthermore, we show that pharmacological inhibition of SUMOylation reduces RBPJ occupancy at Notch target genes.ConclusionsWe propose that the PRC1.6 complex and its conjugated SUMO-modifications provide a scaffold that is recognized by RBPJ and promotes its recruitment to Notch target genes.

scholarly journals PRMT6 activates cyclin D1 expression in conjunction with the transcription factor LEF1

Oncogenesis ◽  
2021 ◽  
Vol 10 (5) ◽  
Author(s):  
Lucas Schneider ◽  
Stefanie Herkt ◽  
Lei Wang ◽  
Christine Feld ◽  
Josephine Wesely ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Transcription Factors ◽  
Cyclin D1 ◽  
Cell Fate ◽  
Target Genes ◽  
Specific Gene ◽  
Cell Fate Decisions ◽  
Rational Development ◽  
Differentiation And Proliferation

AbstractThe establishment of cell type specific gene expression by transcription factors and their epigenetic cofactors is central for cell fate decisions. Protein arginine methyltransferase 6 (PRMT6) is an epigenetic regulator of gene expression mainly through methylating arginines at histone H3. This way it influences cellular differentiation and proliferation. PRMT6 lacks DNA-binding capability but is recruited by transcription factors to regulate gene expression. However, currently only a limited number of transcription factors have been identified, which facilitate recruitment of PRMT6 to key cell cycle related target genes. Here, we show that LEF1 contributes to the recruitment of PRMT6 to the central cell cycle regulator CCND1 (Cyclin D1). We identified LEF1 as an interaction partner of PRMT6. Knockdown of LEF1 or PRMT6 reduces CCND1 expression. This is in line with our observation that knockdown of PRMT6 increases the number of cells in G1 phase of the cell cycle and decreases proliferation. These results improve the understanding of PRMT6 activity in cell cycle regulation. We expect that these insights will foster the rational development and usage of specific PRMT6 inhibitors for cancer therapy.

scholarly journals Notch Signaling Regulation in HCC: From Hepatitis Virus to Non-Coding RNAs

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 521
Author(s):  
Catia Giovannini ◽  
Francesca Fornari ◽  
Fabio Piscaglia ◽  
Laura Gramantieri
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Hepatitis Virus ◽  
Notch Pathway ◽  
Notch Receptor ◽  
Gamma Secretase ◽  
Stem Cell Maintenance ◽  
Pathway Activation ◽  
Promising Therapeutic Approach ◽  
Conserved Genes

The Notch family includes evolutionary conserved genes that encode for single-pass transmembrane receptors involved in stem cell maintenance, development and cell fate determination of many cell lineages. Upon activation by different ligands, and depending on the cell type, Notch signaling plays pleomorphic roles in hepatocellular carcinoma (HCC) affecting neoplastic growth, invasion capability and stem like properties. A specific knowledge of the deregulated expression of each Notch receptor and ligand, coupled with resultant phenotypic changes, is still lacking in HCC. Therefore, while interfering with Notch signaling might represent a promising therapeutic approach, the complexity of Notch/ligands interactions and the variable consequences of their modulations raises concerns when performed in undefined molecular background. The gamma-secretase inhibitors (GSIs), representing the most utilized approach for Notch inhibition in clinical trials, are characterized by important adverse effects due to the non-specific nature of GSIs themselves and to the lack of molecular criteria guiding patient selection. In this review, we briefly summarize the mechanisms involved in Notch pathway activation in HCC supporting the development of alternatives to the γ-secretase pan-inhibitor for HCC therapy.

Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 1154-1162 ◽  
Author(s):  
Wei Zheng ◽  
Tuomas Tammela ◽  
Masahiro Yamamoto ◽  
Andrey Anisimov ◽  
Tanja Holopainen ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Notch Pathway ◽  
Lymphatic Vessels ◽  
Soluble Form ◽  
Fibrin Gel ◽  
3 Dimensional ◽  
Endothelial Growth Factor

Abstract Notch signaling plays a central role in cell-fate determination, and its role in lateral inhibition in angiogenic sprouting is well established. However, the role of Notch signaling in lymphangiogenesis, the growth of lymphatic vessels, is poorly understood. Here we demonstrate Notch pathway activity in lymphatic endothelial cells (LECs), as well as induction of delta-like ligand 4 (Dll4) and Notch target genes on stimulation with VEGF or VEGF-C. Suppression of Notch signaling by a soluble form of Dll4 (Dll4-Fc) synergized with VEGF in inducing LEC sprouting in 3-dimensional (3D) fibrin gel assays. Expression of Dll4-Fc in adult mouse ears promoted lymphangiogenesis, which was augmented by coexpressing VEGF. Lymphangiogenesis triggered by Notch inhibition was suppressed by a monoclonal VEGFR-2 Ab as well as soluble VEGF and VEGF-C/VEGF-D ligand traps. LECs transduced with Dll4 preferentially adopted the tip cell position over nontransduced cells in 3D sprouting assays, suggesting an analogous role for Dll4/Notch in lymphatic and blood vessel sprouting. These results indicate that the Notch pathway controls lymphatic endothelial quiescence, and explain why LECs are poorly responsive to VEGF compared with VEGF-C. Understanding the role of the Notch pathway in lymphangiogenesis provides further insight for the therapeutic manipulation of the lymphatic vessels.

scholarly journals Functional Promiscuity of Gene Regulation by Serpentine Receptors in Dictyostelium discoideum

1998 ◽  
Vol 18 (10) ◽  
pp. 5744-5749 ◽  
Author(s):  
Irene Verkerke-Van Wijk ◽  
Ji-Yun Kim ◽  
Raymond Brandt ◽  
Peter N. Devreotes ◽  
Pauline Schaap
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Dictyostelium Discoideum ◽  
Developmental Regulation ◽  
Mutant Cell ◽  
Gene Induction ◽  
Specific Gene ◽  
Wild Type ◽  
Animal Development ◽  
Camp Stimulation

ABSTRACT Serpentine receptors such as smoothened and frizzled play important roles in cell fate determination during animal development. InDictyostelium discoideum, four serpentine cyclic AMP (cAMP) receptors (cARs) regulate expression of multiple classes of developmental genes. To understand their function, it is essential to know whether each cAR is coupled to a specific gene regulatory pathway or whether specificity results from the different developmental regulation of individual cARs. To distinguish between these possibilities, we measured gene induction in car1 car3 double mutant cell lines that express equal levels of either cAR1, cAR2, or cAR3 under a constitutive promoter. We found that all cARs efficiently mediate both aggregative gene induction by cAMP pulses and induction of postaggregative and prespore genes by persistent cAMP stimulation. Two exceptions to this functional promiscuity were observed. (i) Only cAR1 can mediate adenosine inhibition of cAMP-induced prespore gene expression, a phenomenon that was found earlier in wild-type cells. cAR1’s mediation of adenosine inhibition suggests that cAR1 normally mediates prespore gene induction. (ii) Only cAR2 allows entry into the prestalk pathway. Prestalk gene expression is induced by differentiation-inducing factor (DIF) but only after cells have been prestimulated with cAMP. We found that DIF-induced prestalk gene expression is 10 times higher in constitutive cAR2 expressors than in constitutive cAR1 or cAR3 expressors (which still have endogenous cAR2), suggesting that cAR2 mediates induction of DIF competence. Since in wild-type slugs cAR2 is expressed only in anterior cells, this could explain the so far puzzling observations that prestalk cells differentiate at the anterior region but that DIF levels are actually higher at the posterior region. After the initial induction of DIF competence, cAMP becomes a repressor of prestalk gene expression. This function can again be mediated by cAR1, cAR2, and cAR3.

scholarly journals Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

2015 ◽  
Vol 112 (5) ◽  
pp. E402-E409 ◽  
Author(s):  
Marcelo Boareto ◽  
Mohit Kumar Jolly ◽  
Mingyang Lu ◽  
José N. Onuchic ◽  
Cecilia Clementi ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Tumor Stroma ◽  
Notch Receptor ◽  
Toggle Switch ◽  
Cell Fate Determination ◽  
Asymmetric Effect ◽  
Fate Determination

Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically––it represses Delta, but activates Jagged. Although the dynamical role of Notch–Jagged signaling remains elusive, it is widely recognized that Notch–Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt––Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state––a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor–stroma cross-talk, which frequently entails Notch–Jagged communication.

Interaction of the transforming growth factor-β and Notch signaling pathways in the regulation of granulosa cell proliferation

2016 ◽  
Vol 28 (12) ◽  
pp. 1873 ◽  
Author(s):  
Xiao-Feng Sun ◽  
Xing-Hong Sun ◽  
Shun-Feng Cheng ◽  
Jun-Jie Wang ◽  
Yan-Ni Feng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Growth Factor ◽  
Granulosa Cell ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Notch Pathway ◽  
Transforming Growth Factor Β ◽  
Notch Signalling ◽  
Signalling Pathways

The Notch and transforming growth factor (TGF)-β signalling pathways play an important role in granulosa cell proliferation. However, the mechanisms underlying the cross-talk between these two signalling pathways are unknown. Herein we demonstrated a functional synergism between Notch and TGF-β signalling in the regulation of preantral granulosa cell (PAGC) proliferation. Activation of TGF-β signalling increased hairy/enhancer-of-split related with YRPW motif 2 gene (Hey2) expression (one of the target genes of the Notch pathway) in PAGCs, and suppression of TGF-β signalling by Smad3 knockdown reduced Hey2 expression. Inhibition of the proliferation of PAGCs by N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butylester (DAPT), an inhibitor of Notch signalling, was rescued by both the addition of ActA and overexpression of Smad3, indicating an interaction between the TGF-β and Notch signalling pathways. Co-immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) assays were performed to identify the point of interaction between the two signalling pathways. CoIP showed direct protein–protein interaction between Smad3 and Notch2 intracellular domain (NICD2), whereas ChIP showed that Smad3 could be recruited to the promoter regions of Notch target genes as a transcription factor. Therefore, the findings of the present study support the idea that nuclear Smad3 protein can integrate with NICD2 to form a complex that acts as a transcription factor to bind specific DNA motifs in Notch target genes, such as Hey1 and Hey2, and thus participates in the transcriptional regulation of Notch target genes, as well as regulation of the proliferation of PAGCs.

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

Development ◽  
1995 ◽  
Vol 121 (11) ◽  
pp. 3745-3752 ◽  
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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