scholarly journals Logic programming to predict cell fate patterns and retrodict genotypes in organogenesis

2014 ◽  
Vol 11 (98) ◽  
pp. 20140245 ◽  
Author(s):  
Benjamin A. Hall ◽  
Ethan Jackson ◽  
Alex Hajnal ◽  
Jasmin Fisher
Keyword(s):  
Cell Fate ◽  
Formal Analysis ◽  
Cell Fate Determination ◽  
Logic Programs ◽  
Vulval Development ◽  
Analysis Techniques ◽  
C Elegans ◽  
Vulval Precursor Cells ◽  
Powerful Approach ◽  
Temporal And Spatial

Caenorhabditis elegans vulval development is a paradigm system for understanding cell differentiation in the process of organogenesis. Through temporal and spatial controls, the fate pattern of six cells is determined by the competition of the LET-23 and the Notch signalling pathways. Modelling cell fate determination in vulval development using state-based models, coupled with formal analysis techniques, has been established as a powerful approach in predicting the outcome of combinations of mutations. However, computing the outcomes of complex and highly concurrent models can become prohibitive. Here, we show how logic programs derived from state machines describing the differentiation of C. elegans vulval precursor cells can increase the speed of prediction by four orders of magnitude relative to previous approaches. Moreover, this increase in speed allows us to infer, or ‘retrodict’, compatible genomes from cell fate patterns. We exploit this technique to predict highly variable cell fate patterns resulting from dig-1 reduced-function mutations and let-23 mosaics. In addition to the new insights offered, we propose our technique as a platform for aiding the design and analysis of experimental data.

scholarly journals The C. elegans Mi-2 chromatin-remodelling proteins function in vulval cell fate determination

Development ◽  
2000 ◽  
Vol 127 (24) ◽  
pp. 5277-5284 ◽  
Author(s):  
T. von Zelewsky ◽  
F. Palladino ◽  
K. Brunschwig ◽  
H. Tobler ◽  
A. Hajnal ◽  
...  
Keyword(s):  
Cell Fate ◽  
Central Component ◽  
Cell Fate Determination ◽  
Nurd Complex ◽  
Fate Determination ◽  
C Elegans ◽  
Vulval Precursor Cells ◽  
The Subject ◽  
Biochemical Analyses ◽  
Ras Signalling

The Mi-2 protein is the central component of the recently isolated NuRD nucleosome remodelling and histone deacetylase complex. Although the NuRD complex has been the subject of extensive biochemical analyses, little is known about its biological function. Here we show that the two C. elegans Mi-2 homologues, LET-418 and CHD-3, play essential roles during development. The two proteins possess both shared and unique functions during vulval cell fate determination, including antagonism of the Ras signalling pathway required for vulval cell fate induction and the proper execution of the 2 degrees cell fate of vulval precursor cells, a process under the control of LIN-12 Notch signalling.

scholarly journals Cell fate patterning during C. elegans vulval development

Development ◽  
1993 ◽  
Vol 119 (Supplement) ◽  
pp. 9-18 ◽  
Author(s):  
Russell J. Hill ◽  
Paul W. Sternberg
Keyword(s):  
Cell Fate ◽  
Short Range ◽  
Precursor Cells ◽  
Cell Fates ◽  
Vulval Development ◽  
C Elegans ◽  
Vulval Precursor Cells ◽  
Combined Action ◽  
Anchor Cell ◽  
Inductive Signal

Precursor cells of the vulva of the C. elegans hermaphrodite choose between two vulval cell fates (1° and 2°) and a non-vulval epidermal fate (3°) in response to three intercellular signals. An inductive signal produced by the anchor cell induces the vulval precursors to assume the 1° and 2° vulval fates. This inductive signal is an EGF-like growth factor encoded by the gene lin-3. An inhibitory signal mediated by lin-15, and which may originate from the surrounding epidermis, prevents the vulval precursors from assuming vulval fates in the absence of the inductive signal. A short range lateral signal, which acts through the gene lin-12, regulates the pattern of 1° and 2° fates assumed by the induced vulval precursors. The combined action of the three signals precisely directs the six vulval precursors to adopt a 3° 3° 2° 1° 2 ° 3° pattern of fates. The amount of inductive signal produced by the anchor cell appears to determine the number or vulval precursors that assume vulval fates. The three induced vulval precursors most proximal to the anchor cell are proposed to adopt the 2° 1° 2° pattern of fates in response to a gradient of the inductive signal and also in response to lateral signalling that inhibits adjacent vulval precursor cells from both assuming the 1° fate.

The beta-catenin homolog BAR-1 and LET-60 Ras coordinately regulate the Hox gene lin-39 during Caenorhabditis elegans vulval development

Development ◽  
1998 ◽  
Vol 125 (18) ◽  
pp. 3667-3680 ◽  
Author(s):  
D.M. Eisenmann ◽  
J.N. Maloof ◽  
J.S. Simske ◽  
C. Kenyon ◽  
S.K. Kim
Keyword(s):  
Signaling Pathway ◽  
Cell Fate ◽  
Precursor Cell ◽  
Ras Signaling ◽  
Beta Catenin ◽  
Cell Fates ◽  
Vulval Development ◽  
Hox Gene ◽  
C Elegans ◽  
Vulval Precursor Cell

In C. elegans, the epithelial Pn.p cells adopt either a vulval precursor cell fate or fuse with the surrounding hypodermis (the F fate). Our results suggest that a Wnt signal transduced through a pathway involving the beta-catenin homolog BAR-1 controls whether P3.p through P8.p adopt the vulval precursor cell fate. In bar-1 mutants, P3.p through P8.p can adopt F fates instead of vulval precursor cell fates. The Wnt/bar-1 signaling pathway acts by regulating the expression of the Hox gene lin-39, since bar-1 is required for LIN-39 expression and forced lin-39 expression rescues the bar-1 mutant phenotype. LIN-39 activity is also regulated by the anchor cell signal/let-23 receptor tyrosine kinase/let-60 Ras signaling pathway. Our genetic and molecular experiments show that the vulval precursor cells can integrate the input from the BAR-1 and LET-60 Ras signaling pathways by coordinately regulating activity of the common target LIN-39 Hox.

The Hox gene lin-39 is required during C. elegans vulval induction to select the outcome of Ras signaling

Development ◽  
1998 ◽  
Vol 125 (2) ◽  
pp. 181-190 ◽  
Author(s):  
J.N. Maloof ◽  
C. Kenyon
Keyword(s):  
Body Region ◽  
Ras Signaling ◽  
Cell Fates ◽  
Vulval Development ◽  
Ras Pathway ◽  
Hox Gene ◽  
C Elegans ◽  
Cell Divisions ◽  
Ras Activation ◽  
Vulval Precursor Cells

The Ras signaling pathway specifies a variety of cell fates in many organisms. However, little is known about the genes that function downstream of the conserved signaling cassette, or what imparts the specificity necessary to cause Ras activation to trigger different responses in different tissues. In C. elegans, activation of the Ras pathway induces cells in the central body region to generate the vulva. Vulval induction takes place in the domain of the Hox gene lin-39. We have found that lin-39 is absolutely required for Ras signaling to induce vulval development. During vulval induction, the Ras pathway, together with basal lin-39 activity, up-regulates lin-39 expression in vulval precursor cells. We find that if lin-39 function is absent at this time, no vulval cell divisions occur. Furthermore, if lin-39 is replaced with the posterior Hox gene mab-5, then posterior structures are induced instead of a vulva. Our findings suggest that in addition to permitting vulval cell divisions to occur, lin-39 is also required to specify the outcome of Ras signaling by selectively activating vulva-specific genes.

scholarly journals The Signaling Network Controlling C. elegans Vulval Cell Fate Patterning

2018 ◽  
Vol 6 (4) ◽  
pp. 30 ◽  
Author(s):  
Hanna Shin ◽  
David Reiner
Keyword(s):  
Cell Fate ◽  
Signaling Network ◽  
Signaling Cascades ◽  
Cell Fates ◽  
C Elegans ◽  
Differentiated Cells ◽  
Vulval Precursor Cells ◽  
Cell Patterns ◽  
History Of ◽  
Anchor Cell

EGF, emitted by the Anchor Cell, patterns six equipotent C. elegans vulval precursor cells to assume a precise array of three cell fates with high fidelity. A group of core and modulatory signaling cascades forms a signaling network that demonstrates plasticity during the transition from naïve to terminally differentiated cells. In this review, we summarize the history of classical developmental manipulations and molecular genetics experiments that led to our understanding of the signals governing this process, and discuss principles of signal transduction and developmental biology that have emerged from these studies.

scholarly journals RNA methylation in mammalian development and cancer

2021 ◽  
Author(s):  
Peizhe Song ◽  
Subiding Tayier ◽  
Zhihe Cai ◽  
Guifang Jia
Keyword(s):  
Cell Fate ◽  
Cancer Progression ◽  
Rna Modification ◽  
Biological Processes ◽  
Cell Fate Determination ◽  
Mammalian Development ◽  
Rna Modifications ◽  
Temporal And Spatial ◽  
Underlying Mechanisms ◽  
Cellular Components

AbstractSimilar to epigenetic DNA and histone modifications, epitranscriptomic modifications (RNA modifications) have emerged as crucial regulators in temporal and spatial gene expression during eukaryotic development. To date, over 170 diverse types of chemical modifications have been identified upon RNA nucleobases. Some of these post-synthesized modifications can be reversibly installed, removed, and decoded by their specific cellular components and play critical roles in different biological processes. Accordingly, dysregulation of RNA modification effectors is tightly orchestrated with developmental processes. Here, we particularly focus on three well-studied RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), and N1-methyladenosine (m1A), and summarize recent knowledge of underlying mechanisms and critical roles of these RNA modifications in stem cell fate determination, embryonic development, and cancer progression, providing a better understanding of the whole association between epitranscriptomic regulation and mammalian development.

scholarly journals Spindle assembly checkpoint strength is governed by cell size and PAR-mediated cell fate determination in C. elegans

2017 ◽  
Author(s):  
Abigail R. Gerhold ◽  
Vincent Poupart ◽  
Jean-Claude Labbé ◽  
Paul S. Maddox
Keyword(s):  
Cell Size ◽  
Cell Fate ◽  
Genome Stability ◽  
Spindle Assembly Checkpoint ◽  
Asymmetric Cell Division ◽  
Spindle Assembly ◽  
Cell Types ◽  
Cell Fate Determination ◽  
C Elegans ◽  
Cell Divisions

AbstractThe spindle assembly checkpoint (SAC) is a conserved mitotic regulator that preserves genome stability. Despite its central role in preserving the fidelity of mitosis, the strength of the SAC varies widely between cell types. How the SAC is adapted to different cellular contexts remains largely unknown. Here we show that both cell size and cell fate impact SAC strength. While smaller cells have a stronger SAC, cells with a germline fate show increased SAC activity relative to their somatic counterparts across all cell sizes. We find that enhanced SAC activity in the germline blastomere P1 requires proper specification of cell fate downstream of the conserved PAR polarity proteins, supporting a model in which checkpoint factors are distributed asymmetrically during early germ cell divisions. Our results indicate that size scaling of SAC activity is modulated by cell fate and reveal a novel interaction between asymmetric cell division and the SAC.

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.

scholarly journals Insulated Switches: Dual-Function Protein RalGEFRGL-1 Promotes Developmental Fidelity

2020 ◽  
Vol 21 (20) ◽  
pp. 7610 ◽  
Author(s):  
Tam Duong ◽  
Neal R. Rasmussen ◽  
David J. Reiner
Keyword(s):  
Birth Defects ◽  
Dual Function ◽  
Wild Type ◽  
Cell Fates ◽  
Vulval Development ◽  
C Elegans ◽  
Vulval Precursor Cells ◽  
Anchor Cell ◽  
The Impact ◽  
Wild Type Control

The C. elegans vulva is an excellent model for the study of developmental biology and cell–cell signaling. The developmental induction of vulval precursor cells (VPCs) to assume the 3°-3°-2°-1°-2°-3° patterning of cell fates occurs with 99.8% accuracy. During C. elegans vulval development, an EGF signal from the anchor cell initiates the activation of RasLET-60 > RafLIN-45 > MEKMEK-2 > ERKMPK-1 signaling cascade to induce the 1° cell. The presumptive 1° cell signals its two neighboring cells via NotchLIN-12 to develop 2° cells. In addition, RasLET-60 switches effectors to RalGEFRGL-1 > RalRAL-1 to promote 2° fate. Shin et al. (2019) showed that RalGEFRGL-1 is a dual-function protein in VPCs fate patterning. RalGEFRGL-1 functions as a scaffold for PDKPDK-1 > AktAKT-1/2 modulatory signaling to promote 1° fate in addition to propagating the RasLET-60 modulatory signal through RalRAL-1 to promote 2° fate. The deletion of RalGEFRGL-1 increases the frequency of VPC patterning errors 15-fold compared to the wild-type control. We speculate that RalGEFRGL-1 represents an “insulated switch”, whereby the promotion of one signaling activity curtails the promotion of the opposing activity. This property might increase the impact of the switch on fidelity more than two separately encoded proteins could. Understanding how developmental fidelity is controlled will help us to better understand the origins of cancer and birth defects, which occur in part due to the misspecification of cell fates.

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