scholarly journals The C. elegans Notch proteins LIN-12 and GLP-1 are tuned to lower force thresholds for activation than Drosophila Notch

2021 ◽  
Author(s):  
Paul D. Langridge ◽  
Jessica Yu Chan ◽  
Alejandro Garcia-Diaz ◽  
Iva Greenwald ◽  
Gary Struhl
Keyword(s):  
Signal Transduction ◽  
Cell Fate ◽  
Cleavage Site ◽  
Regulatory Region ◽  
Force Level ◽  
Cell Fate Decisions ◽  
C Elegans ◽  
Protease Cleavage ◽  
Cytosolic Domains ◽  
Pulling Force

AbstractThe conserved transmembrane receptor Notch mediates cell fate decisions in all animals. In the absence of ligand, a Negative Regulatory Region (NRR) in the Notch ectodomain adopts an autoinhibited confirmation, masking an ADAM protease cleavage site [1, 2]; ligand binding makes the cleavage site accessible, leading to shedding of the Notch ectodomain as the first step of signal transduction [3, 4]. In Drosophila and vertebrates, the ligands are all single-pass transmembrane Delta/Serrate/LAG-2 (DSL) proteins; the endocytic adaptor Epsin binds to the ubiquitinated intracellular domain, and the resulting Clathrin-mediated endocytosis exerts a “pulling force” that exposes the cleavage site in the NRR [4–6]. However, in C. elegans, the presence of natural secreted DSL proteins [7] and other observations suggested that Epsin-mediated endocytosis may not be required to activate the Notch proteins LIN-12 and GLP-1. Here, we confirm that neither Epsin nor the cytosolic domains of DSL proteins are required for Notch signaling in C. elegans. Furthermore, we provide evidence that the NRRs of LIN-12 and GLP-1 are tuned to a lower force level than the NRR of Drosophila Notch. Finally, we show that adding a Leucine “plug” that occludes the cleavage site in vertebrate and Drosophila Notch proteins but is absent in the C. elegans Notch proteins [1, 2] renders the LIN-12 and GLP-1 NRRs dependent on Epsin-mediated ligand endocytosis, indicating that greater force is now required to expose the cleavage site. Thus, the NRRs of LIN-12 and GLP-1 appear to be tuned to a lower force threshold, accounting for the different requirements for signaling in C. elegans.

scholarly journals Posttranscriptional regulation of T helper cell fate decisions

2018 ◽  
Vol 217 (8) ◽  
pp. 2615-2631 ◽  
Author(s):  
Kai P. Hoefig ◽  
Vigo Heissmeyer
Keyword(s):  
Signal Transduction ◽  
Transcription Factors ◽  
T Cell ◽  
Cell Fate ◽  
T Helper Cell ◽  
T Cell Subsets ◽  
Helper Cell ◽  
Regulation Of Transcription ◽  
T Helper ◽  
Cell Fate Decisions

T helper cell subsets orchestrate context- and pathogen-specific responses of the immune system. They mostly do so by secreting specific cytokines that attract or induce activation and differentiation of other immune or nonimmune cells. The differentiation of T helper 1 (Th1), Th2, T follicular helper, Th17, and induced regulatory T cell subsets from naive T cells depends on the activation of intracellular signal transduction cascades. These cascades originate from T cell receptor and costimulatory receptor engagement and also receive critical input from cytokine receptors that sample the cytokine milieu within secondary lymphoid organs. Signal transduction then leads to the expression of subset-specifying transcription factors that, in concert with other transcription factors, up-regulate downstream signature genes. Although regulation of transcription is important, recent research has shown that posttranscriptional and posttranslational regulation can critically shape or even determine the outcome of Th cell differentiation. In this review, we describe how specific microRNAs, long noncoding RNAs, RNA-binding proteins, and ubiquitin-modifying enzymes regulate their targets to skew cell fate decisions.

scholarly journals hecd-1 Modulates Notch Activity in Caenorhabditis elegans

2015 ◽  
Vol 5 (3) ◽  
pp. 353-359 ◽  
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.

scholarly journals unc-37/Groucho and lsy-22/AES repress Wnt target genes in C. elegans asymmetric cell divisions

2022 ◽  
Author(s):  
Kimberly N. Bekas ◽  
Bryan T. Phillips
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Gene ◽  
Target Genes ◽  
Intermediate Cell ◽  
Beta Catenin ◽  
Cell Fate Decisions ◽  
C Elegans ◽  
Somatic Gonad ◽  
Seam Cell

Asymmetric cell division (ACD) is a fundamental mechanism of developmental cell fate specification and adult tissue homeostasis. In C. elegans, the Wnt/beta-catenin asymmetry (WβA) pathway regulates ACDs throughout embryonic and larval development. Under control of Wnt ligand-induced polarity, the transcription factor TCF/POP-1 functions with the coactivator beta-catenin/SYS-1 to activate gene expression in the signaled cell or, in absence of the coactivator, to repress Wnt target genes in the nascent unsignaled daughter cell. To date, a broad investigation of Groucho function in WβA is lacking and the function of the short Groucho AES homolog, lsy-22 has only been evaluated in C. elegans neuronal cell fate decisions. Further, there is conflicting evidence showing TCF utilizing Groucho-mediated repression may be either aided or repressed by addition of AES subfamily of Groucho proteins. Here we demonstrate a genetic interaction between Groucho repressors and TCF/POP-1 in ACDs in the somatic gonad, the seam hypodermal stem cell lineage and the early embryo. Specifically, in the somatic gonad lineage, the signaled cell fate increases after individual and double Groucho loss of function, representing the first demonstration of Groucho function in wild-type WβA ACD. Further, WβA target gene misexpression occurs at a higher rate than DTC fate changes, suggesting derepression generates an intermediate cell fate. In seam cell ACD, loss of Groucho unc-37 or Groucho-like lsy-22 in a pop-1(RNAi) hypomorphic background enhances a pop-1 seam cell expansion and target gene misregulation. Moreover, while POP-1 depletion in lsy-22 null mutants yielded an expected increase in seam cells we observed a surprising seam cell decrease in the unc-37 null subjected to POP-1 depletion. This phenotype may be due to UNC-37 regulation of pop-1 expression in this tissue since we find misregulation of POP-1 in unc-37 mutants. Lastly, Groucho functions in embryonic endoderm development since we observe ectopic endoderm target gene expression in lsy-22(ot244) heterozygotes and unc-37(tm4649) heterozygotes subjected to intermediate levels of hda-1(RNAi). Together, these data indicate Groucho repressor modulation of cell fate via regulation of POP-1/TCF repression is widespread in asymmetric cell fate decisions and suggests a novel role of LSY-22 as a bona fide TCF repressor. As AES Grouchos are well-conserved, our model of combinatorial TCF repression by both Gro/TLE and AES warrants further investigation. 

scholarly journals The C. elegans vulval induction gene lin-2 encodes a member of the MAGUK family of cell junction proteins

Development ◽  
1996 ◽  
Vol 122 (1) ◽  
pp. 97-111 ◽  
Author(s):  
R. Hoskins ◽  
A.F. Hajnal ◽  
S.A. Harp ◽  
S.K. Kim
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Cell Fate ◽  
Receptor Tyrosine Kinase ◽  
Basal Membrane ◽  
Cell Junctions ◽  
Cell Junction ◽  
Relative Molecular Mass ◽  
C Elegans ◽  
Signal Transduction Proteins

The lin-2 gene is required for the induction of the Caenorhabditis elegans vulva. Vulval development is initiated by a signal from the anchor cell that is transduced by a receptor tyrosine kinase/Ras pathway. We show that lin-2 acts in the vulval precursor cell P6.p, downstream of lin-3 EGF and upstream of let-60 ras, to allow expression of the 1 degrees cell fate. lin-2 encodes a protein of relative molecular mass 109,000 (LIN-2A) with regions of similarity to CaM kinase II and membrane-associated guanylate kinases. Mutant lin-2 transgenes designed to lack either protein kinase or guanylate kinase activity are functional, indicating that LIN-2A has a structural rather than an enzymatic role in vulval induction. Most or all identified membrane-associated guanylate kinases are components of cell junctions, including vertebrate tight junctions and arthropod septate junctions in epithelia. Thus, LIN-2A may be a component of the cell junctions of the epithelial vulval precursor cells that is required for signaling by the receptor tyrosine kinase LET-23. We propose that LIN-2A is required for the localization of one or more signal transduction proteins (such as LET-23) to either the basal membrane domain or the cell junctions, and that mislocalization of signal transduction proteins in lin-2 mutants interferes with vulval induction.

scholarly journals REF-1, a protein with two bHLH domains, alters the pattern of cell fusion in C. elegans by regulating Hox protein activity

Development ◽  
2001 ◽  
Vol 128 (10) ◽  
pp. 1793-1804 ◽  
Author(s):  
S. Alper ◽  
C. Kenyon
Keyword(s):  
Cell Fate ◽  
Cell Fusion ◽  
Hox Genes ◽  
Body Axis ◽  
Body Region ◽  
Protein Activity ◽  
Cell Fate Decisions ◽  
C Elegans ◽  
Helix Loop Helix ◽  
Body Regions

Hox genes control the choice of cell fates along the anteroposterior (AP) body axis of many organisms. In C. elegans, two Hox genes, lin-39 and mab-5, control the cell fusion decision of the 12 ventrally located Pn.p cells. Specific Pn.p cells fuse with an epidermal syncytium, hyp7, in a sexually dimorphic pattern. In hermaphrodites, Pn.p cells in the mid-body region remain unfused whereas in males, Pn.p cells adopt an alternating pattern of syncytial and unfused fates. The complexity of these fusion patterns arises because the activities of these two Hox proteins are regulated in a sex-specific manner. MAB-5 activity is inhibited in hermaphrodite Pn.p cells and thus MAB-5 normally only affects the male Pn.p fusion pattern. Here we identify a gene, ref-1, that regulates the hermaphrodite Pn.p cell fusion pattern largely by regulating MAB-5 activity in these cells. Mutation of ref-1 also affects the fate of other epidermal cells in distinct AP body regions. ref-1 encodes a protein with two basic helix-loop-helix domains distantly related to those of the hairy/Enhancer of split family. ref-1, and another hairy homolog, lin-22, regulate similar cell fate decisions in different body regions along the C. elegans AP body axis.

Interchangeability of Caenorhabditis elegans DSL proteins and intrinsic signalling activity of their extracellular domains in vivo

Development ◽  
1995 ◽  
Vol 121 (12) ◽  
pp. 4275-4282 ◽  
Author(s):  
K. Fitzgerald ◽  
I. Greenwald
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Cell Interactions ◽  
Regulatory Sequences ◽  
Cell Fate Decisions ◽  
C Elegans ◽  
Dsl Ligands ◽  
Mediate Cell ◽  
Intracellular Domains

Ligands of the Delta/Serrate/lag-2 (DSL) family and their receptors, members of the lin-12/Notch family, mediate cell-cell interactions that specify cell fate in invertebrates and vertebrates. In C. elegans, two DSL genes, lag-2 and apx-1, influence different cell fate decisions during development. Here we show that APX-1 can fully substitute for LAG-2 when expressed under the control of lag-2 regulatory sequences. In addition, we demonstrate that truncated forms lacking the transmembrane and intracellular domains of both LAG-2 and APX-1 can also substitute for endogenous lag-2 activity. Moreover, we provide evidence that these truncated forms are secreted and able to activate LIN-12 and GLP-1 ectopically. Finally, we show that expression of a secreted DSL domain alone may enhance endogenous LAG-2 signalling. Our data suggest ways that activated forms of DSL ligands in other systems may be created.

LIN-12 protein expression and localization during vulval development in C. elegans

Development ◽  
1998 ◽  
Vol 125 (16) ◽  
pp. 3101-3109 ◽  
Author(s):  
D. Levitan ◽  
I. Greenwald
Keyword(s):  
Cell Fate ◽  
Feedback Mechanism ◽  
Precursor Cell ◽  
Vulval Development ◽  
Ras Pathway ◽  
Cell Fate Decisions ◽  
C Elegans ◽  
Somatic Gonad ◽  
Multiple Cell ◽  
Vulval Precursor Cell

We have used a LIN-12::GFP fusion protein to examine LIN-12 accumulation during cell fate decisions important for vulval development. During the naturally variable anchor cell (AC)/ventral uterine precursor cell (VU) decision of the somatic gonad, a transcription-based feedback mechanism biases two equivalent cells so that one becomes the AC while the other becomes a VU. LIN-12::GFP accumulation reflects lin-12 transcription: LIN-12::GFP is initially present in both cells, but disappears from the presumptive AC and becomes restricted to the presumptive VU. During vulval precursor cell (VPC) fate determination, six equipotential cells uniformly transcribe lin-12 and have invariant fates that are specified by multiple cell-cell interactions. The pattern of LIN-12::GFP accumulation in VPCs and in the VPC lineages is dynamic and does not always reflect lin-12 transcription. In particular, LIN-12::GFP is expressed initially in all six VPCs, but appears to be reduced specifically in P6.p as a consequence of the activation of the Ras pathway by an EGF-like inductive signal from the AC. We propose that downregulation of LIN-12 stability or translation in response to inductive signalling helps impose a bias on lateral signalling and contributes to the invariant pattern of VPC fates.

Translational control in the C. elegans hermaphrodite germ line

Genome ◽  
2010 ◽  
Vol 53 (2) ◽  
pp. 83-102 ◽  
Author(s):  
Hilary Racher ◽  
Dave Hansen
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Translational Control ◽  
Translational Regulation ◽  
Developmental Stages ◽  
Germ Line ◽  
Control Of Gene Expression ◽  
Cell Fate Decisions ◽  
C Elegans ◽  
Mrna Targets

The formation of a fully developed gamete from an undifferentiated germ cell requires progression through numerous developmental stages and cell fate decisions. The precise timing and level of gene expression guides cells through these stages. Translational regulation is highly utilized in the germ line of many species, including Caenorhabditis elegans , to regulate gene expression and ensure the proper formation of gametes. In this review, we discuss some of the developmental stages and cell fate decisions involved in the formation of functional gametes in the C. elegans germ line in which translational control has been implicated. These stages include the mitosis versus meiosis decision, the sperm/oocyte decision, and gamete maturation. We also discuss some of the techniques used to identify mRNA targets; the identification of these targets is necessary to clearly understand the role each RNA-binding protein plays in these decisions. Relatively few mRNA targets have been identified, thus providing a major focus for future research. Finally, we propose some reasons why translational control may be utilized so heavily in the germ line. Given that many species have this substantial reliance on translational regulation for the control of gene expression in the germ line, an understanding of translational regulation in the C. elegans germ line is likely to increase our understanding of gamete formation in general.

scholarly journals Optogenetic Approaches for the Spatiotemporal Control of Signal Transduction Pathways

2021 ◽  
Vol 22 (10) ◽  
pp. 5300
Author(s):  
Markus M. Kramer ◽  
Levin Lataster ◽  
Wilfried Weber ◽  
Gerald Radziwill
Keyword(s):  
Signal Transduction ◽  
Cell Fate ◽  
Tyrosine Kinases ◽  
Intracellular Signaling ◽  
Cellular Response ◽  
Cell Receptor ◽  
Effector Proteins ◽  
Signal Transduction Pathways ◽  
Cell Fate Decisions ◽  
Spatiotemporal Control

Biological signals are sensed by their respective receptors and are transduced and processed by a sophisticated intracellular signaling network leading to a signal-specific cellular response. Thereby, the response to the signal depends on the strength, the frequency, and the duration of the stimulus as well as on the subcellular signal progression. Optogenetic tools are based on genetically encoded light-sensing proteins facilitating the precise spatiotemporal control of signal transduction pathways and cell fate decisions in the absence of natural ligands. In this review, we provide an overview of optogenetic approaches connecting light-regulated protein-protein interaction or caging/uncaging events with steering the function of signaling proteins. We briefly discuss the most common optogenetic switches and their mode of action. The main part deals with the engineering and application of optogenetic tools for the control of transmembrane receptors including receptor tyrosine kinases, the T cell receptor and integrins, and their effector proteins. We also address the hallmarks of optogenetics, the spatial and temporal control of signaling events.

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