scholarly journals Inhibition of Wnt signalling by Notch via two distinct mechanisms

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ahmet Acar ◽  
Ana Hidalgo-Sastre ◽  
Michael K. Leverentz ◽  
Christopher G. Mills ◽  
Simon Woodcock ◽  
...  
Keyword(s):  
Cell Fate ◽  
Membrane Fraction ◽  
Transcriptional Activity ◽  
Cell Types ◽  
Wnt Signalling ◽  
Signalling Pathways ◽  
Adult Tissue ◽  
Cell Fate Decisions ◽  
Dsl Ligands ◽  
Opposing Effects

AbstractNotch and Wnt are two essential signalling pathways that help to shape animals during development and to sustain adult tissue homeostasis. Although they are often active at the same time within a tissue, they typically have opposing effects on cell fate decisions. In fact, crosstalk between the two pathways is important in generating the great diversity of cell types that we find in metazoans. Several different mechanisms have been proposed that allow Notch to limit Wnt signalling, driving a Notch-ON/Wnt-OFF state. Here we explore these different mechanisms in human cells and demonstrate two distinct mechanisms by which Notch itself, can limit the transcriptional activity of β-catenin. At the membrane, independently of DSL ligands, Notch1 can antagonise β-catenin activity through an endocytic mechanism that requires its interaction with Deltex and sequesters β-catenin into the membrane fraction. Within the nucleus, the intracellular domain of Notch1 can also limit β-catenin induced transcription through the formation of a complex that requires its interaction with RBPjκ. We believe these mechanisms contribute to the robustness of cell-fate decisions by sharpening the distinction between opposing Notch/Wnt responses.

scholarly journals Inhibition of Wnt signalling by Notch via two distinct mechanisms

2020 ◽  
Author(s):  
Ahmet Acar ◽  
Ana Hidalgo-Sastre ◽  
Michael K. Leverentz ◽  
Christopher G. Mills ◽  
Simon Woodcock ◽  
...  
Keyword(s):  
Cell Fate ◽  
Membrane Fraction ◽  
Transcriptional Activity ◽  
Cell Types ◽  
Wnt Signalling ◽  
Signalling Pathways ◽  
Adult Tissue ◽  
Cell Fate Decisions ◽  
Dsl Ligands ◽  
Opposing Effects

SummaryNotch and Wnt are two essential signalling pathways that help to shape animals during development and to sustain adult tissue homeostasis. Although, they are often active at the same time within a tissue, they typically have opposing effects on cell fate decisions. In fact, crosstalk between the two pathways is important in generating the great diversity of cell types that we find in metazoans. However, several different mechanisms have been proposed that allow Notch to limit Wnt signalling, driving a Notch-ON/Wnt-OFF state. Here we explore these different mechanisms in vertebrate cells and demonstrate two distinct mechanisms by which Notch itself, can limit the transcriptional activity of β-catenin. At the membrane, independently of DSL ligands, Notch1 can antagonise β-catenin activity through an endocytosis mediated mechanism that is dependent upon its interaction with Deltex and sequesters β-catenin into the membrane fraction. Within the nucleus, the intracellular domain of Notch1 can also limit β-catenin induced transcription through the formation of a complex that requires its interaction with RBPjκ. We believe these mechanisms contribute to the robustness of cell-fate decisions by sharpening the distinction between opposing Notch/Wnt responses.

scholarly journals Interactions between Nodal and Wnt signalling Drive Robust Symmetry-Breaking and Axial Organisation in Gastruloids (Embryonic Organoids)

2016 ◽  
Author(s):  
D.A. Turner ◽  
C.R. Glodowski ◽  
L. Alonso-Crisostomo ◽  
P. Baillie-Johnson ◽  
P.C. Hayward ◽  
...  
Keyword(s):  
Pattern Formation ◽  
Symmetry Breaking ◽  
Cell Fate ◽  
Embryonic Stem ◽  
Early Embryo ◽  
Model System ◽  
Wnt Signalling ◽  
Signalling Pathways ◽  
Cell Fate Decisions ◽  
Three Body

AbstractGeneration of asymmetry within the early embryo is a critical step in the establishment of the three body axes, providing a reference for the patterning of the organism. To study the establishment of asymmetry and the development of the anteroposterior axis (AP) in culture, we utilised our ‘Gastruloid’ model system. ‘Gastruloids’, highly reproducible embryonic organoids formed from aggregates of mouse embryonic stem cells, display symmetry-breaking, polarised gene expression and axial development, mirroring the processes on a time-scale similar to that of the mouse embyro. Using Gastruloids formed from mouse ESCs containing reporters for Wnt, FGF and Nodal signalling, we were able to quantitatively assess the contribution of these signalling pathways to the establishment of asymmetry through single time-point and live-cell fluorescence microscopy.During the first 24-48h of culture, interactions between the Wnt/β-Catenin and Nodal/TGF/β signalling pathways promote the initial symmetry-breaking event, manifested through polarised Brachyury (T/Bra) expression. Neither BMP nor FGF signalling is required for the establishment of asymmetry, however Wnt signalling is essential for the amplification and stability of the initial patterning event. Additionally, low, endogenous levels of FGF (24-48h) has a role in the amplification of the established pattern at later time-points.Our results confirm that Gastruloids behave like epiblast cells in the embryo, leading us to translate the processes and signalling involved in pattern formation of Gastruloids in culture to the development of the embryo, firmly establishing Gastruloids as a highly reproducible, robust model system for studying cell fate decisions and early pattern formation in culture.

scholarly journals The Roles of Chromatin Accessibility in Regulating the Candida albicans White-Opaque Phenotypic Switch

2021 ◽  
Vol 7 (1) ◽  
pp. 37
Author(s):  
Mohammad N. Qasim ◽  
Ashley Valle Arevalo ◽  
Clarissa J. Nobile ◽  
Aaron D. Hernday
Keyword(s):  
Candida Albicans ◽  
Cell Fate ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Phenotypic Switching ◽  
Phenotypic Switch ◽  
Chromatin Remodelers ◽  
Environmental Signals ◽  
Cell Fate Decisions ◽  
Simple Model System

Candida albicans, a diploid polymorphic fungus, has evolved a unique heritable epigenetic program that enables reversible phenotypic switching between two cell types, referred to as “white” and “opaque”. These cell types are established and maintained by distinct transcriptional programs that lead to differences in metabolic preferences, mating competencies, cellular morphologies, responses to environmental signals, interactions with the host innate immune system, and expression of approximately 20% of genes in the genome. Transcription factors (defined as sequence specific DNA-binding proteins) that regulate the establishment and heritable maintenance of the white and opaque cell types have been a primary focus of investigation in the field; however, other factors that impact chromatin accessibility, such as histone modifying enzymes, chromatin remodelers, and histone chaperone complexes, also modulate the dynamics of the white-opaque switch and have been much less studied to date. Overall, the white-opaque switch represents an attractive and relatively “simple” model system for understanding the logic and regulatory mechanisms by which heritable cell fate decisions are determined in higher eukaryotes. Here we review recent discoveries on the roles of chromatin accessibility in regulating the C. albicans white-opaque phenotypic switch.

scholarly journals Non-cell-autonomous promotion of pluripotency induction mediated by YAP

2018 ◽  
Author(s):  
Amaleah Hartman ◽  
Xiao Hu ◽  
Xinyue Chen ◽  
Anna E. Eastman ◽  
Cindy Yang ◽  
...  
Keyword(s):  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Cell Types ◽  
Matricellular Proteins ◽  
Fate Control ◽  
Promotional Effect ◽  
Cellular Context ◽  
Opposing Effects ◽  
Cell Fate Control ◽  
Heterologous Cell

SUMMARYWhile Yes-associated protein (YAP) antagonizes pluripotency during early embryogenesis, it has also been shown to promote stemness of multiple stem cell types, including pluripotent stem cells. Whether cellular context underlies these distinct functions of YAP in pluripotency remains unclear. Here, we establish that depending on the specific cells in which it is expressed, YAP exhibits opposing effects on pluripotency induction from somatic cells. Specifically, YAP inhibits pluripotency induction cell-autonomously but promotes it non-cell-autonomously. For its non-cell-autonomous role, YAP alters the expression of many secreted and matricellular proteins including CYR61, which recapitulates the promotional effect when added as a recombinant protein. Thus, we define a unique YAP-driven non-cell-autonomous process that enhances pluripotency induction. Our work highlights the importance of considering the distinct contributions from heterologous cell types in deciphering the mechanism of cell fate control and calls for careful re-examination of the co-existing bystander cells in complex cultures or tissues.

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

Development ◽  
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.

scholarly journals Do Neural Stem Cells Have a Choice? Heterogenic Outcome of Cell Fate Acquisition in Different Injury Models

2019 ◽  
Vol 20 (2) ◽  
pp. 455 ◽  
Author(s):  
Felix Beyer ◽  
Iria Samper Agrelo ◽  
Patrick Küry
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Ex Vivo ◽  
Meta Analysis ◽  
Cell Types ◽  
Adult Brain ◽  
Repair Capacity ◽  
Cell Fate Decisions ◽  
Limiting Parameters

The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter.

scholarly journals Hypoxia-Inducible Factors 1α and 2α Regulate Trophoblast Differentiation

2005 ◽  
Vol 25 (23) ◽  
pp. 10479-10491 ◽  
Author(s):  
Karen D. Cowden Dahl ◽  
Benjamin H. Fryer ◽  
Fiona A. Mack ◽  
Veerle Compernolle ◽  
Emin Maltepe ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cell Types ◽  
Hypoxia Inducible Factors ◽  
Low Oxygen ◽  
Placental Development ◽  
Cell Fates ◽  
Trophoblast Stem Cells ◽  
Cell Fate Decisions ◽  
Hypoxic Environment ◽  
Life Threatening

ABSTRACT Placental development initially occurs in a low-oxygen (O2) or hypoxic environment. In this report we show that two hypoxia-inducible factors (HIFs), HIF1α and HIF2α, are essential for determining murine placental cell fates. HIF is a heterodimer composed of HIFα and HIFβ (ARNT) subunits. Placentas from Arnt − / − and Hif1α − / − Hif2α −/− embryos exhibit defective placental vascularization and aberrant cell fate adoption. HIF regulation of Mash2 promotes spongiotrophoblast differentiation, a prerequisite for trophoblast giant cell differentiation. In the absence of Arnt or Hifα, trophoblast stem cells fail to generate these cell types and become labyrinthine trophoblasts instead. Therefore, HIF mediates placental morphogenesis, angiogenesis, and cell fate decisions, demonstrating that O2 tension is a critical regulator of trophoblast lineage determination. This novel genetic approach provides new insights into the role of O2 tension in the development of life-threatening pregnancy-related diseases such as preeclampsia.

scholarly journals Niche mediated integrin signaling supports steady state hematopoiesis in spleen

2020 ◽  
Author(s):  
Shubham Haribhau Mehatre ◽  
Irene Mariam Roy ◽  
Atreyi Biswas ◽  
Devila Prit ◽  
Sarah Schouteden ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cell Types ◽  
Integrin Signaling ◽  
White Pulp ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Functional Regulation

AbstractOutside-in integrin signaling regulates cell fate decisions in a variety of cell types, including hematopoietic stem cells (HSCs). Our earlier published studies showed that interruption of Periostin (POSTN) and Integrin-αv (ITGAV) interaction induces faster proliferation in HSCs with developmental stage dependent functional effects. Here, we examined the role of POSTN-ITGAV axis in lympho-hematopoietic activity in spleen that hosts rare population of HSCs, the functional regulation of which is not clearly known. Vav-iCre mediated deletion of Itgav in hematopoietic system led to higher proliferation rates, resulting in increased frequency of primitive HSCs in adult spleen. However, in vitro CFU-C assays demonstrated a poorer differentiation potential following Itgav deletion. This also led to a decrease in the white pulp area with a significant decline in the B-cell numbers. Systemic deletion of its ligand, POSTN, phenocopied the effects noted in Vav-Itgav−/− mice. Histological examination of Postn deficient spleen also showed increase in the spleen trabecular areas. Surprisingly, these were the myofibroblasts of the trabecular and capsular areas that expressed high levels of POSTN within the spleen tissue. In addition, vascular smooth muscle cells also expressed POSTN. Through CFU-S12 assays, we showed that hematopoietic support potential of stroma in Postn deficient splenic hematopoietic niche was defective. Overall, we demonstrate that POSTN-ITGAV interaction plays important role in spleen lympho-hematopoiesis.

scholarly journals Epigenetic Control of Mesenchymal Stromal Cell Fate Decision

2021 ◽  
Author(s):  
Haoli Ying ◽  
Ruolang Pan ◽  
Ye Chen
Keyword(s):  
Cell Fate ◽  
Molecular Mechanisms ◽  
Epigenetic Modification ◽  
Cell Types ◽  
Connective Tissues ◽  
Differentiation Potential ◽  
Cell Fate Decisions ◽  
Fate Decision ◽  
Msc Differentiation

Mesenchymal stem cells (MSCs) are progenitors of connective tissues, which have emerged as important tools for tissue engineering owing to their differentiation potential in various cell types. The therapeutic utility of MSCs hinges upon our understanding of the molecular mechanisms involved in cellular fate decisions. Thus, the elucidation of the regulation of MSC differentiation has attracted increasing attention in recent years. A variety of external cues contribute to the process of MSC differentiation, including chemical, physical, and biological factors. Among the multiple factors that are known to affect cell fate decisions, the epigenetic regulation of MSC differentiation has become a research hotspot. In this chapter, we summarize recent progress in the determination of the effects of epigenetic modification on the multilineage differentiation of MSCs.

Position dependent control of cell fate in the Fucus embryo: role of intercellular communication

Development ◽  
1998 ◽  
Vol 125 (11) ◽  
pp. 1999-2008 ◽  
Author(s):  
F.Y. Bouget ◽  
F. Berger ◽  
C. Brownlee
Keyword(s):  
Cell Wall ◽  
Pattern Formation ◽  
Cell Fate ◽  
Intercellular Communication ◽  
Cell Types ◽  
Early Embryo ◽  
Cell Contact ◽  
Dependent Manner ◽  
Intact Cells ◽  
Cell Fate Decisions

The early embryo of the brown alga Fucus comprises two cell types, i. e. rhizoid and thallus which are morphogically and cytologically distinguishable. Previous work has pointed to the cell wall as a source of position-dependent information required for polarisation and fate determination in the zygote and 2-celled embryo. In this study we have analysed the mechanism(s) of cell fate control and pattern formation at later embryonic stages using a combination of laser microsurgery and microinjection. The results indicate that the cell wall is required for maintenance of pre-existing polarity in isolated intact cells. However, all cell types ultimately have the capacity to re-differentiate or regenerate rhizoid cells in response to ablation of neighbouring cells. This regeneration is regulated in a position-dependent manner and is strongly influenced by intercellular communication, probably involving transport or diffusion of inhibitory signals which appear to be essential for regulation of cell fate decisions. This type of cell-to-cell communication does not involve symplastic transport or direct cell-cell contact inhibition. Apoplastic diffusible gradients appear to be involved in pattern formation in the multicellular embryo.

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