Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans.

Genetics ◽  
1993 ◽  
Vol 135 (3) ◽  
pp. 765-783 ◽  
Author(s):  
M Sundaram ◽  
I Greenwald
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Gene Dosage ◽  
Egg Laying ◽  
Loss Of Function ◽  
Cell Fate Decision ◽  
Cell Fates ◽  
Cell Fate Decisions ◽  
Suppressor Mutations ◽  
Fate Decision

Abstract The lin-12 gene of Caenorhabditis elegans is thought to encode a receptor which mediates cell-cell interactions required to specify certain cell fates. Reversion of the egg-laying defective phenotype caused by a hypomorphic lin-12 allele identified rare extragenic suppressor mutations in five genes, sel-1, sel-9, sel-10, sel-11 and sel(ar40) (sel = suppressor and/or enhancer of lin-12). Mutations in each of these sel genes suppress defects associated with reduced lin-12 activity, and enhance at least one defect associated with elevated lin-12 activity. None of the sel mutations cause any obvious phenotype in a wild-type background. Gene dosage experiments suggest that sel-1 and sel(ar40) mutations are reduction-of-function mutations, while sel-9 and sel-11 mutations are gain-of-function mutations. sel-1, sel-9, sel-11 and sel(ar40) mutations do not suppress amorphic lin-12 alleles, while sel-10 mutations are able to bypass partially the requirement for lin-12 activity in at least one cell fate decision. sel-1, sel-9, sel-10, sel-11 and sel(ar40) mutations are also able to suppress the maternal-effect lethality caused by a partial loss-of-function allele of glp-1, a gene that is both structurally and functionally related to lin-12. These sel genes may therefore function in both lin-12 and glp-1 mediated cell fate decisions.

scholarly journals Variability in β-catenin pulse dynamics in a stochastic cell fate decision in C. elegans

2018 ◽  
Author(s):  
Jason R. Kroll ◽  
Jasonas Tsiaxiras ◽  
Jeroen S. van Zon
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Cell Fusion ◽  
Precursor Cell ◽  
Cell Fate Decision ◽  
Absolute Level ◽  
Cell Fate Decisions ◽  
Pulse Dynamics ◽  
Significant Variability ◽  
Fate Decision

AbstractDuring development, cell fate decisions are often highly stochastic, but with the frequency of the different possible fates tightly controlled. To understand how signaling networks control the cell fate frequency of such random decisions, we studied the stochastic decision of the Caenorhabditis elegans P3.p cell to either fuse to the hypodermis or assume vulva precursor cell fate. Using time-lapse microscopy to measure the single-cell dynamics of two key inhibitors of cell fusion, the Hox gene LIN-39 and Wnt signaling through the β-catenin BAR-1, we uncovered significant variability in the dynamics of LIN-39 and BAR-1 levels. Most strikingly, we observed that BAR-1 accumulated in a single, 1-4 hour pulse at the time of the P3.p cell fate decision, with strong variability both in pulse slope and time of pulse onset. We found that the time of BAR-1 pulse onset was delayed relative to the time of cell fusion in mutants with low cell fusion frequency, linking BAR-1 pulse timing to cell fate outcome. Overall, a model emerged where animal-to-animal variability in LIN-39 levels and BAR-1 pulse dynamics biases cell fate by modulating their absolute level at the time cell fusion is induced. Our results highlight that timing of cell signaling dynamics, rather than its average level or amplitude, could play an instructive role in determining cell fate.Article summaryWe studied the stochastic decision of the Caenorhabditis elegans P3.p cell to either fuse to the hypodermis or assume vulva precursor cell fate. We uncovered significant variability in the dynamics of LIN-39/Hox and BAR-1/β-catenin levels, two key inhibitors of cell fusion. Surprisingly, we observed that BAR-1 accumulated in a 1-4 hour pulse at the time of the P3.p cell fate decision, with variable pulse slope and time of pulse onset. Our work suggests a model where animal-to-animal variability in LIN-39 levels and BAR-1 pulse dynamics biases cell fate by modulating their absolute level at the time cell fusion is induced.

scholarly journals Identification and Characterization of Genes That Interact With lin-12 in Caenorhabditis elegans

Genetics ◽  
1997 ◽  
Vol 147 (4) ◽  
pp. 1675-1695 ◽  
Author(s):  
Frans E Tax ◽  
James H Thomas ◽  
Edwin L Ferguson ◽  
H Robert Horvitzt
Keyword(s):  
Cell Fate ◽  
Low Frequency ◽  
Signal Transduction Pathway ◽  
Temperature Shift ◽  
Egg Laying ◽  
Null Alleles ◽  
Temperature Sensitive ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Suppressor Mutations

Abstract We identified and characterized 14 extragenic mutations that suppressed the dominant egg-laying defect of certain lin-12 gain-of-function mutations. These suppressors defined seven genes: sup-l7, lag-2, sel-4, sel-5, sel-6, sel-7 and sel-8. Mutations in six of the genes are recessive suppressors, whereas the two mutations that define the seventh gene, lag-2, are semi-dominant suppressors. These suppressor mutations were able to suppress other lin-12 gain-of-function mutations. The suppressor mutations arose at a very low frequency per gene, 10-50 times below the typical loss-of-function mutation frequency. The suppressor mutations in sup1 7 and lag-2 were shown to be rare non-null alleles, and we present evidence that null mutations in these two genes cause lethality. Temperature-shift studies for two suppressor genes, sup1 7and lag-2, suggest that both genes act at approximately the same time as lin-12in specifying a cell fate. Suppressor alleles of six of these genes enhanced a temperature-sensitive loss-of-function allele of glp-1, a gene related to lin-12 in structure and function. Our analysis of these suppressors suggests that the majority of these genes are part of a shared lin-12/glp-1 signal transduction pathway, or act to regulate the expression or stability of lin-12 and glp-1.

scholarly journals Cell fate clusters in ICM organoids arise from cell fate heredity and division: a modelling approach

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tim Liebisch ◽  
Armin Drusko ◽  
Biena Mathew ◽  
Ernst H. K. Stelzer ◽  
Sabine C. Fischer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Division ◽  
Cell Fate ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Cell Lineage ◽  
Cell Fate Decision ◽  
Cell Fate Decisions ◽  
Chemical Signalling ◽  
Fate Decision

AbstractDuring the mammalian preimplantation phase, cells undergo two subsequent cell fate decisions. During the first decision, the trophectoderm and the inner cell mass are formed. Subsequently, the inner cell mass segregates into the epiblast and the primitive endoderm. Inner cell mass organoids represent an experimental model system, mimicking the second cell fate decision. It has been shown that cells of the same fate tend to cluster stronger than expected for random cell fate decisions. Three major processes are hypothesised to contribute to the cell fate arrangements: (1) chemical signalling; (2) cell sorting; and (3) cell proliferation. In order to quantify the influence of cell proliferation on the observed cell lineage type clustering, we developed an agent-based model accounting for mechanical cell–cell interaction, i.e. adhesion and repulsion, cell division, stochastic cell fate decision and cell fate heredity. The model supports the hypothesis that initial cell fate acquisition is a stochastically driven process, taking place in the early development of inner cell mass organoids. Further, we show that the observed neighbourhood structures can emerge solely due to cell fate heredity during cell division.

scholarly journals A single-cell resolved cell-cell communication model explains lineage commitment in hematopoiesis

Development ◽  
2021 ◽  
Vol 148 (24) ◽  
Author(s):  
Megan K. Rommelfanger ◽  
Adam L. MacLean
Keyword(s):  
Cell Fate ◽  
Cell Communication ◽  
Communication Model ◽  
Cell Fate Decision ◽  
Cell Coupling ◽  
Environmental Signals ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Fate Decision ◽  
Cell Cell

ABSTRACT Cells do not make fate decisions independently. Arguably, every cell-fate decision occurs in response to environmental signals. In many cases, cell-cell communication alters the dynamics of the internal gene regulatory network of a cell to initiate cell-fate transitions, yet models rarely take this into account. Here, we have developed a multiscale perspective to study the granulocyte-monocyte versus megakaryocyte-erythrocyte fate decisions. This transition is dictated by the GATA1-PU.1 network: a classical example of a bistable cell-fate system. We show that, for a wide range of cell communication topologies, even subtle changes in signaling can have pronounced effects on cell-fate decisions. We go on to show how cell-cell coupling through signaling can spontaneously break the symmetry of a homogenous cell population. Noise, both intrinsic and extrinsic, shapes the decision landscape profoundly, and affects the transcriptional dynamics underlying this important hematopoietic cell-fate decision-making system. This article has an associated ‘The people behind the papers’ interview.

EGF receptor attenuates Dpp signaling and helps to distinguish the wing and leg cell fates in Drosophila

Development ◽  
2000 ◽  
Vol 127 (17) ◽  
pp. 3769-3776 ◽  
Author(s):  
K. Kubota ◽  
S. Goto ◽  
K. Eto ◽  
S. Hayashi
Keyword(s):  
Spatial Distribution ◽  
Cell Fate ◽  
Receptor Tyrosine Kinase ◽  
Egf Receptor ◽  
Homeobox Gene ◽  
Cell Fate Decision ◽  
Cell Fates ◽  
Dorsoventral Axis ◽  
Fate Decision ◽  
Number Of Cells

Wing and leg precursors of Drosophila are recruited from a common pool of ectodermal cells expressing the homeobox gene Dll. Induction by Dpp promotes this cell fate decision toward the wing and proximal leg. We report here that the receptor tyrosine kinase EGFR antagonizes the wing-promoting function of Dpp and allows recruitment of leg precursor cells from uncommitted ectodermal cells. By monitoring the spatial distribution of cells responding to Dpp and EGFR, we show that nuclear transduction of the two signals peaks at different position along the dorsoventral axis when the fates of wing and leg discs are specified and that the balance of the two signals assessed within the nucleus determines the number of cells recruited to the wing. Differential activation of the two signals and the cross talk between them critically affect this cell fate choice.

scholarly journals Accessible chromatin reveals regulatory mechanisms underlying cell fate decisions during early embryogenesis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tongqiang Fan ◽  
Youjun Huang
Keyword(s):  
Cell Fate ◽  
Chromatin Accessibility ◽  
Early Embryogenesis ◽  
Regulatory Sequences ◽  
Cell Fate Decision ◽  
Joint Research ◽  
Cell Fate Decisions ◽  
Fate Decision ◽  
Multiple Species ◽  
Accessible Chromatin

AbstractThis study was conducted to investigate epigenetic landscape across multiple species and identify transcription factors (TFs) and their roles in controlling cell fate decision events during early embryogenesis. We made a comprehensively joint-research of chromatin accessibility of five species during embryogenesis by integration of ATAC-seq and RNA-seq datasets. Regulatory roles of candidate early embryonic TFs were investigated. Widespread accessible chromatin in early embryos overlapped with putative cis-regulatory sequences. Sets of cell-fate-determining TFs were identified. YOX1, a key cell cycle regulator, were found to homologous to clusters of TFs that are involved in neuron and epidermal cell-fate determination. Our research provides an intriguing insight into evolution of cell-fate decision during early embryogenesis among organisms.

scholarly journals A genetic analysis of deltex and its interaction with the Notch locus in Drosophila melanogaster.

Genetics ◽  
1992 ◽  
Vol 131 (1) ◽  
pp. 99-112 ◽  
Author(s):  
M J Gorman ◽  
J R Girton
Keyword(s):  
Cell Fate ◽  
Developmental Pathways ◽  
Phenotypic Characterization ◽  
Loss Of Function ◽  
Cell Fates ◽  
Cone Cells ◽  
Notch Gene ◽  
Notch Locus ◽  
Fate Decision

Abstract During Drosophila development networks of genes control the developmental pathways that specify cell fates. The Notch gene is a well characterized member of some cell fate pathways, and several other genes belonging to these same pathways have been identified because they share a neurogenic null phenotype with Notch. However, it is unlikely that the neurogenic genes represent all of the genes in these pathways. The goal of this research was to use a genetic approach to identify and characterize one of the other genes that acts with Notch to specify cell fate. Mutant alleles of genes in the same pathway should have phenotypes similar to Notch alleles and should show phenotypic interactions with Notch alleles. With this approach we identified the deltex gene as a potential cell fate gene. An extensive phenotypic characterization of loss-of-function deltex phenotypes showed abnormalities (such as thick wing veins, double bristles and extra cone cells) that suggest that deltex is involved in cell fate decision processes. Phenotypic interactions between deltex and Notch as seen in double mutants showed that Notch and deltex do not code for duplicate functions and that the two genes function together in many different developing tissues. The results of these investigations lead to the conclusion that the deltex gene functions with the Notch gene in one or more developmental pathways to specify cell fate.

scholarly journals Quantifying Waddington landscapes and paths of non-adiabatic cell fate decisions for differentiation, reprogramming and transdifferentiation

2013 ◽  
Vol 10 (89) ◽  
pp. 20130787 ◽  
Author(s):  
Chunhe Li ◽  
Jin Wang
Keyword(s):  
Decision Making ◽  
Stem Cell ◽  
Cell Fate ◽  
Intermediate State ◽  
Regulatory Networks ◽  
Experimental Studies ◽  
Cell Fate Decision ◽  
Cell Fate Decisions ◽  
Decision Making Processes ◽  
Fate Decision

Cellular differentiation, reprogramming and transdifferentiation are determined by underlying gene regulatory networks. Non-adiabatic regulation via slow binding/unbinding to the gene can be important in these cell fate decision-making processes. Based on a stem cell core gene network, we uncovered the stem cell developmental landscape. As the binding/unbinding speed decreases, the landscape topography changes from bistable attractors of stem and differentiated states to more attractors of stem and other different cell states as well as substates. Non-adiabaticity leads to more differentiated cell types and provides a natural explanation for the heterogeneity observed in the experiments. We quantified Waddington landscapes with two possible cell fate decision mechanisms by changing the regulation strength or regulation timescale (non-adiabaticity). Transition rates correlate with landscape topography through barrier heights between different states and quantitatively determine global stability. We found the optimal speeds of these cell fate decision-making processes. We quantified biological paths and predict that differentiation and reprogramming go through an intermediate state (IM1), whereas transdifferentiation goes through another intermediate state (IM2). Some predictions are confirmed by recent experimental studies.

Cell cycle-dependent sequencing of cell fate decisions in Caenorhabditis elegans vulva precursor cells

Development ◽  
1999 ◽  
Vol 126 (9) ◽  
pp. 1947-1956 ◽  
Author(s):  
V. Ambros
Keyword(s):  
Cell Cycle ◽  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Precursor Cells ◽  
S Phase ◽  
Cycle Phase ◽  
Cell Fates ◽  
Cell Fate Decisions ◽  
Cycle Arrest ◽  
Cycle Dependent

In Caenorhabditis elegans, the fates of the six multipotent vulva precursor cells (VPCs) are specified by extracellular signals. One VPC expresses the primary (1 degrees) fate in response to a Ras-mediated inductive signal from the gonad. The two VPCs flanking the 1 degrees cell each express secondary (2 degrees) fates in response to lin-12-mediated lateral signaling. The remaining three VPCs each adopt the non-vulval tertiary (3 degrees) fate. Here I describe experiments examining how the selection of these vulval fates is affected by cell cycle arrest and cell cycle-restricted lin-12 activity. The results suggest that lin-12 participates in two developmental decisions separable by cell cycle phase: lin-12 must act prior to the end of VPC S phase to influence a 1 degrees versus 2 degrees cell fate choice, but must act after VPC S phase to influence a 3 degrees versus 2 degrees cell fate choice. Coupling developmental decisions to cell cycle transitions may provide a mechanism for prioritizing or ordering choices of cell fates for multipotential cells.

scholarly journals Genetic and phenotypic studies of hypomorphic lin-12 mutants in Caenorhabditis elegans.

Genetics ◽  
1993 ◽  
Vol 135 (3) ◽  
pp. 755-763 ◽  
Author(s):  
M Sundaram ◽  
I Greenwald
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
System Development ◽  
Egg Laying ◽  
Cell Fates ◽  
Hypomorphic Allele ◽  
High Penetrance ◽  
Hypomorphic Alleles ◽  
Null Mutants

Abstract The lin-12 gene of Caenorhabditis elegans is thought to encode a receptor for intercellular signals that specify certain cell fates during development. We describe several alleles of lin-12 that reduce but do not eliminate lin-12 activity (hypomorphic alleles). These alleles cause a novel egg-laying defective (Egl) phenotype in hermaphrodites as well as incompletely penetrant cell fate transformations seen with high penetrance in lin-12 null mutants. Characterization of the Egl phenotype revealed additional roles of lin-12 in the development of the egg-laying system that were not apparent from studying lin-12 null mutants: lin-12 activity is required for proper early vulval morphogenesis as well as for some unknown later aspect of egg-laying system development. Reversion of the Egl phenotype caused by one lin-12 hypomorphic allele was used to identify potential interacting genes as described in the accompanying paper.

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