scholarly journals A novel mutant allele uncouples brassinosteroid-dependent and independent functions of BRI1

2019 ◽  
Author(s):  
Eleonore Holzwart ◽  
Nina Glöckner ◽  
Herman Höfte ◽  
Klaus Harter ◽  
Sebastian Wolf
Keyword(s):  
Cell Fate ◽  
Recessive Trait ◽  
Feedback Information ◽  
Surface Receptors ◽  
Growth Defects ◽  
Wide Range ◽  
Independent Functions ◽  
Procambial Cell ◽  
Plasma Membrane Receptor ◽  
Response Phenotype

AbstractPlants depend on an array of cell surface receptors to integrate extracellular signals with developmental programs. One of the best-studied receptors is BRASSINOSTEROID INSENSITIVE 1 (BRI1), which upon binding of its hormone ligands forms a complex with shape-complimentary co-receptors and initiates a signal transduction cascade leading to a wide range of responses. BR biosynthetic and receptor mutants have similar growth defects on the macroscopic level, which had initially led to the assumption of a largely linear signalling pathway. However, recent evidence suggests that BR signalling is interconnected with a number of other pathways through a variety of different mechanisms. We recently described that feedback information from the cell wall is integrated at the level of the receptor complex through interaction with RLP44. Moreover, BRI1 is required for a second function of RLP44, the control of procambial cell fate. Here, we report on a BRI1 mutant, bri1cnu4, which differentially affects canonical BR signalling and RLP44 function in the vasculature. While BR signalling is only mildly impaired, bri1cnu4 mutants show ectopic xylem in the position of procambium. Mechanistically, this is explained by an increased association of RLP44 and the mutated BRI1 protein, which prevents the former from acting in vascular cell fate maintenance. Consistent with this, the mild BR response phenotype of bri1cnu4 is a recessive trait, whereas the RLP44-mediated xylem phenotype is semi-dominant. Our results highlight the complexity of plant plasma membrane receptor function and provide a tool to dissect BR signalling-related roles of BRI1 from its non-canonical functions.One sentence summaryA novel mutant allows to dissect brassinosteroid signalling related and non-canonical functions of the receptor-like kinase BRI1.

scholarly journals The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

2021 ◽  
Vol 22 (13) ◽  
pp. 6857
Author(s):  
Samantha Bruno ◽  
Manuela Mancini ◽  
Sara De Santis ◽  
Cecilia Monaldi ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cell Fate ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Bone Marrow Microenvironment ◽  
Metabolic Adaptation ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.

scholarly journals Cyto-friendly polymerization at cell surfaces modulates cell fate by clustering cell-surface receptors

2020 ◽  
Vol 11 (16) ◽  
pp. 4221-4225 ◽  
Author(s):  
Jing Qi ◽  
Weishuo Li ◽  
Xiaoling Xu ◽  
Feiyang Jin ◽  
Di Liu ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Fate ◽  
Cell Surface Receptors ◽  
Cell Surfaces ◽  
Receptor Clustering ◽  
Surface Polymerization ◽  
Surface Receptors ◽  
Anti Cd20 ◽  
In Cells

Cell-surface polymerization of anti-CD20 aptamer modified macromer to induce CD20 receptor clustering, and effectively initiate the apoptotic signals in cells.

scholarly journals Genomic analyses reveal a conserved glutathione homeostasis pathway in the invertebrate chordate Ciona intestinalis

2009 ◽  
Vol 39 (3) ◽  
pp. 183-194 ◽  
Author(s):  
Gerardo M. Nava ◽  
David Y. Lee ◽  
Javier H. Ospina ◽  
Shi-Ying Cai ◽  
H. Rex Gaskins
Keyword(s):  
Cell Fate ◽  
Molecular Mechanisms ◽  
Ciona Intestinalis ◽  
Phylogenetic Position ◽  
Filter Feeder ◽  
Diverse Range ◽  
Regulatory Pathways ◽  
Wide Range ◽  
Redox Buffer ◽  
Invertebrate Chordate

The major thiol redox buffer glutathione (l-γ-glutamyl-l-cysteinylglycine, GSH) is central to cell fate determination, and thus, associated metabolic and regulatory pathways are exquisitely sensitive to a wide range of environmental cues. An imbalance of cellular redox homeostasis has emerged as a pathologic hallmark of a diverse range of human gene-environment disorders. Despite the central importance of GSH in cellular homeostasis, underlying genetic regulatory pathways remain poorly defined. This report describes the annotation and expression analysis of genes contributing to GSH homeostasis in the invertebrate chordate Ciona intestinalis . A core pathway comprising 19 genes contributing to the biosynthesis of GSH and its use as both a redox buffer and a conjugate in phase II detoxification as well as known transcriptional regulators were analyzed. These genes exhibit a high level of sequence conservation with corresponding human, rat, and mouse homologs and were expressed constitutively in tissues of adult animals. The GSH biosynthetic genes Gclc and Gclm were also responsive to the prototypical antioxidant tert-butylhydroquinone. The present evidence of a conserved GSH homeostasis pathway in C. intestinalis together with its phylogenetic position as a basal chordate and lifestyle as a filter feeder constantly exposed to natural marine toxins introduces this species as an important animal model for defining molecular mechanisms that potentially underlie genetic susceptibility to environmentally associated stress.

scholarly journals Inhibitory activities of short linear motifs underlie Hox interactome specificity in vivo

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Manon Baëza ◽  
Séverine Viala ◽  
Marjorie Heim ◽  
Amélie Dard ◽  
Bruno Hudry ◽  
...  
Keyword(s):  
Cell Fate ◽  
Drosophila Embryo ◽  
Traditional Role ◽  
Hox Proteins ◽  
Short Linear Motifs ◽  
Wide Range ◽  
Mouse Species ◽  
Inhibitory Activities ◽  
Linear Motifs

Hox proteins are well-established developmental regulators that coordinate cell fate and morphogenesis throughout embryogenesis. In contrast, our knowledge of their specific molecular modes of action is limited to the interaction with few cofactors. Here, we show that Hox proteins are able to interact with a wide range of transcription factors in the live Drosophila embryo. In this context, specificity relies on a versatile usage of conserved short linear motifs (SLiMs), which, surprisingly, often restrains the interaction potential of Hox proteins. This novel buffering activity of SLiMs was observed in different tissues and found in Hox proteins from cnidarian to mouse species. Although these interactions remain to be analysed in the context of endogenous Hox regulatory activities, our observations challenge the traditional role assigned to SLiMs and provide an alternative concept to explain how Hox interactome specificity could be achieved during the embryonic development.

scholarly journals The DBL-1/TGF-β signaling pathway regulates pathogen-specific innate immune responses in C. elegans

2021 ◽  
Author(s):  
Bhoomi Madhu ◽  
Tina L. Gumienny
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Signaling Pathway ◽  
Defense Responses ◽  
C Elegans ◽  
Host Immune Responses ◽  
Wide Range ◽  
Independent Functions ◽  
Multiple Cell

Innate immunity in animals is orchestrated by multiple cell signaling pathways, including the TGF-β; superfamily pathway. While the role of TGF-β signaling in innate immunity has been clearly identified, the requirement for this pathway in generating specific, robust responses to different bacterial challenges has not been characterized. Here, we address the role of DBL-1/TGF-β in regulating signature host defense responses to a wide range of bacteria in C. elegans. This work reveals a role of DBL-1/TGF-β in animal survival, organismal behaviors, and molecular responses in different environments. Additionally, we identify a novel role for SMA-4/Smad that suggests both DBL-1/TGF-β-dependent and -independent functions in host avoidance responses. RNA-seq analyses and immunity reporter studies indicate DBL-1/TGF-β differentially regulates target gene expression upon exposure to different bacteria. Furthermore, the DBL-1/TGF-β pathway is itself differentially affected by the bacteria exposure. Collectively, these findings demonstrate bacteria-specific host immune responses regulated by the DBL-1/TGF-β signaling pathway.

Ectopic expression of either the Drosophila gooseberry-distal or proximal gene causes alterations of cell fate in the epidermis and central nervous system

Development ◽  
1994 ◽  
Vol 120 (5) ◽  
pp. 1151-1161 ◽  
Author(s):  
Y. Zhang ◽  
A. Ungar ◽  
C. Fresquez ◽  
R. Holmgren
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cell Fate ◽  
Ectopic Expression ◽  
Cell Fate Specification ◽  
Single Function ◽  
Independent Functions ◽  
Segment Polarity ◽  
The Central Nervous System ◽  
The Common

Previous studies have shown that the segment polarity locus gooseberry, which contains two closely related transcripts gooseberry-proximal and gooseberry-distal, is required for proper development in both the epidermis and the central nervous system of Drosophila. In this study, the roles of the gooseberry proteins in the process of cell fate specification have been examined by generating two fly lines in which either gooseberry-distal or gooseberry-proximal expression is under the control of an hsp70 promoter. We have found that ectopic expression of either gooseberry protein causes cell fate transformations that are reciprocal to those of a gooseberry deletion mutant. Our results suggest that the gooseberry-distal protein is required for the specification of naked cuticle in the epidermis and specific neuroblasts in the central nervous system. These roles may reflect independent functions in neuroblasts and epidermal cells or a single function in the common ectodermal precursor cells. The gooseberry-proximal protein is also found in the same neuroblasts as gooseberry-distal and in the descendants of these cells.

scholarly journals Theoretical study of the impact of adaptation on cell-fate heterogeneity and fractional killing

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Julien Hurbain ◽  
Darka Labavić ◽  
Quentin Thommen ◽  
Benjamin Pfeuty
Keyword(s):  
Cell Fate ◽  
Stochastic Dynamics ◽  
Biochemical Networks ◽  
Stochastic Bifurcation ◽  
Modeling Framework ◽  
Life And Death ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Adaptation Response ◽  
The Impact

Abstract Fractional killing illustrates the cell propensity to display a heterogeneous fate response over a wide range of stimuli. The interplay between the nonlinear and stochastic dynamics of biochemical networks plays a fundamental role in shaping this probabilistic response and in reconciling requirements for heterogeneity and controllability of cell-fate decisions. The stress-induced fate choice between life and death depends on an early adaptation response which may contribute to fractional killing by amplifying small differences between cells. To test this hypothesis, we consider a stochastic modeling framework suited for comprehensive sensitivity analysis of dose response curve through the computation of a fractionality index. Combining bifurcation analysis and Langevin simulation, we show that adaptation dynamics enhances noise-induced cell-fate heterogeneity by shifting from a saddle-node to a saddle-collision transition scenario. The generality of this result is further assessed by a computational analysis of a detailed regulatory network model of apoptosis initiation and by a theoretical analysis of stochastic bifurcation mechanisms. Overall, the present study identifies a cooperative interplay between stochastic, adaptation and decision intracellular processes that could promote cell-fate heterogeneity in many contexts.

scholarly journals Class A Scavenger Receptors Are Used by Frog Virus 3 During Its Cellular Entry

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 93 ◽  
Author(s):  
Nguyen Vo ◽  
Matthew Guerreiro ◽  
Amulya Yaparla ◽  
Leon Grayfer ◽  
Stephanie DeWitte-Orr
Keyword(s):  
Cellular Level ◽  
Scavenger Receptors ◽  
Null Cell ◽  
Cellular Receptors ◽  
Frog Virus 3 ◽  
Frog Virus ◽  
Surface Receptors ◽  
Class A ◽  
Wide Range ◽  
Cellular Entry

Frog virus 3 (FV3) is the type species of the genus Ranavirus (family Iridoviridae). FV3 and FV3-like viruses are globally distributed infectious agents with the capacity to replicate in three vertebrate classes (teleosts, amphibians, and reptiles). At the cellular level, FV3 and FV3-like viruses can infect cells from virtually all vertebrate classes. To date, the cellular receptors that are involved in the FV3 entry process are unknown. Class A scavenger receptors (SR-As) are a family of evolutionarily conserved cell-surface receptors that bind a wide range of chemically distinct polyanionic ligands and can function as cellular receptors for other DNA viruses, including vaccinia virus and herpes simplex virus. The present study aimed to determine whether SR-As are involved in FV3 cellular entry. By using well-defined SR-A competitive and non-competitive ligand-blocking assays and absolute qPCR, we demonstrated that the SR-A competitive ligands drastically reduced the quantities of cell-associated viral loads in frog cells. Moreover, inducing the expression of a human SR-AI in an SR-A null cell line significantly increased FV3–cell association. Together, our results indicate that SR-As are utilized by FV3 during the cellular entry process.

scholarly journals An Essential Role for SNX1 in Lysosomal Sorting of Protease-activated Receptor-1: Evidence for Retromer-, Hrs-, and Tsg101-independent Functions of Sorting Nexins

2006 ◽  
Vol 17 (3) ◽  
pp. 1228-1238 ◽  
Author(s):  
Anuradha Gullapalli ◽  
Breann L. Wolfe ◽  
Courtney T. Griffin ◽  
Terry Magnuson ◽  
JoAnn Trejo
Keyword(s):  
Essential Role ◽  
Resistant Mutant ◽  
Interacting Protein ◽  
Sorting Nexins ◽  
Surface Receptors ◽  
Endosomal Membrane ◽  
Independent Functions ◽  
Lysosomal Sorting ◽  
Protease Activated Receptor 1 ◽  
In Cells

Sorting nexin 1 (SNX1) and SNX2 are the mammalian homologues of the yeast Vps5p retromer component that functions in endosome-to-Golgi trafficking. SNX1 is also implicated in endosome-to-lysosome sorting of cell surface receptors, although its requirement in this process remains to be determined. To assess SNX1 function in endocytic sorting of protease-activated receptor-1 (PAR1), we used siRNA to deplete HeLa cells of endogenous SNX1 protein. PAR1, a G-protein-coupled receptor, is proteolytically activated by thrombin, internalized, sorted predominantly to lysosomes, and efficiently degraded. Strikingly, depletion of endogenous SNX1 by siRNA markedly inhibited agonist-induced PAR1 degradation, whereas expression of a SNX1 siRNA-resistant mutant protein restored agonist-promoted PAR1 degradation in cells lacking endogenous SNX1, indicating that SNX1 is necessary for lysosomal degradation of PAR1. SNX1 is known to interact with components of the mammalian retromer complex and Hrs, an early endosomal membrane-associated protein. However, activated PAR1 degradation was not affected in cells depleted of retromer Vps26/Vps35 subunits, Hrs or Tsg101, an Hrs-interacting protein. We further show that SNX2, which dimerizes with SNX1, is not essential for lysosomal sorting of PAR1, but rather can regulate PAR1 degradation by disrupting endosomal localization of endogenous SNX1 when ectopically expressed. Together, our findings establish an essential role for endogenous SNX1 in sorting activated PAR1 to a distinct lysosomal degradative pathway that is independent of retromer, Hrs, and Tsg101.

scholarly journals The target specificity of the RNA binding protein Pumilio is determined by distinct co-factors

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Sumira Malik ◽  
Wijeong Jang ◽  
Song Yeon Park ◽  
Ji Young Kim ◽  
Ki-Sun Kwon ◽  
...  
Keyword(s):  
Cell Fate ◽  
Rna Binding ◽  
Neural Function ◽  
Target Specificity ◽  
Family Protein ◽  
Wide Range ◽  
Bag Of Marbles ◽  
Translational Regulators ◽  
Underlying Mechanisms ◽  
Puf Family

Abstract Puf family proteins are translational regulators essential to a wide range of biological processes, including cell fate specification, stem cell self-renewal, and neural function. Yet, despite being associated with hundreds of RNAs, the underlying mechanisms of Puf target specification remain to be fully elucidated. In Drosophila, Pumilio – a sole Puf family protein – is known to collaborate with cofactors Nanos (Nos) and Brain Tumor (Brat); however, their roles in target specification are not clearly defined. Here, we identify Bag-of-marbles (Bam) as a new Pum cofactor in repression of Mothers against dpp (mad) mRNAs, for which Nos is known to be dispensable. Notably, our data show that Nos (but not Bam) was required for Pum association with hunchback (hb) mRNAs, a well-known target of Pum and Nos. In contrast, Bam (but not Nos) was required for Pum association with mad mRNAs. These findings show for the first time that Pum target specificity is determined not independently but in collaboration with cofactors.

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