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An Atlas of Network Topologies Reveals Design Principles for Caenorhabditis elegans Vulval Precursor Cell Fate Patterning.

Ping X, Tang C - PLoS ONE (2015)

Bottom Line: We show that the topology derived by mapping currently known biochemical pathways to our model matches one of our identified functional topologies.Furthermore, our robustness analysis predicts a possible missing link related to the lateral antagonism strategy.Overall, we provide a theoretical atlas of all possible functional networks in varying environments, which may guide novel discoveries of the biological interactions in vulval development of Caenorhabditis elegans and related species.

View Article: PubMed Central - PubMed

Affiliation: Center for Quantitative Biology and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.

ABSTRACT
The vulval precursor cell (VPC) fate patterning in Caenorhabditis elegans is a classic model experimental system for cell fate determination and patterning in development. Despite its apparent simplicity (six neighboring cells arranged in one dimension) and many experimental and computational efforts, the patterning strategy and mechanism remain controversial due to incomplete knowledge of the complex biology. Here, we carry out a comprehensive computational analysis and obtain a reservoir of all possible network topologies that are capable of VPC fate patterning under the simulation of various biological environments and regulatory rules. We identify three patterning strategies: sequential induction, morphogen gradient and lateral antagonism, depending on the features of the signal secreted from the anchor cell. The strategy of lateral antagonism, which has not been reported in previous studies of VPC patterning, employs a mutual inhibition of the 2° cell fate in neighboring cells. Robust topologies are built upon minimal topologies with basic patterning strategies and have more flexible and redundant implementations of modular functions. By simulated mutation, we find that all three strategies can reproduce experimental error patterns of mutants. We show that the topology derived by mapping currently known biochemical pathways to our model matches one of our identified functional topologies. Furthermore, our robustness analysis predicts a possible missing link related to the lateral antagonism strategy. Overall, we provide a theoretical atlas of all possible functional networks in varying environments, which may guide novel discoveries of the biological interactions in vulval development of Caenorhabditis elegans and related species.

No MeSH data available.


The C. elegans VPC patterning system and the coarse-grained model.(A) VPC differentiation. (B) Coarse-grained modeling of VPC patterning. The two-node model with 10 links numbered from 1 to 10 is shown in the left panel. Dashed lines represent intercellular interactions and solid lines intracellular interactions. The modeling system of five Pn.p cells along with their initial and target values is shown in the upper-right panel. The ODE functions of two examples are shown in the lower-right panel.
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pone.0131397.g001: The C. elegans VPC patterning system and the coarse-grained model.(A) VPC differentiation. (B) Coarse-grained modeling of VPC patterning. The two-node model with 10 links numbered from 1 to 10 is shown in the left panel. Dashed lines represent intercellular interactions and solid lines intracellular interactions. The modeling system of five Pn.p cells along with their initial and target values is shown in the upper-right panel. The ODE functions of two examples are shown in the lower-right panel.

Mentions: Vulval development in C. elegans has served as a paradigm for cell fate determination [10,11]. The nematode’s vulva is formed from the descendants of six multipotent VPCs, named P3.p to P8.p, that adopt one of three cell fates (Fig 1A). Early evidence showed that their fates depend on their distances to an anchor cell (AC), which is near the VPCs and secretes an epidermal growth factor (EGF) signal [11,12]. The VPC closest to the AC (P6.p) becomes a primary (1°) cell; the VPCs at an intermediate distance (P5.p and P7.p) become secondary (2°) cells; and the more distant ones (P3.p, P4.p and P8.p) become tertiary (3°) cells (Fig 1A). Two important pathways have been uncovered that contribute to the VPC patterning: the inductive signal pathway and the lateral signal pathway [11,13–16]. More specifically, the inductive signal is transduced by the receptor-tyrosine kinase (RTK) pathway with diffusible EGF from the AC as its ligand. The lateral signal is transduced by the Notch pathway between the VPCs themselves, with Notch as its receptor. The ligands of the Notch pathway have two forms: diffusible DSL-1 and membrane-bound LAG-2 and APX-1 [17]. Evidence showed that the two pathways and their crosstalk induce VPC patterning [18].


An Atlas of Network Topologies Reveals Design Principles for Caenorhabditis elegans Vulval Precursor Cell Fate Patterning.

Ping X, Tang C - PLoS ONE (2015)

The C. elegans VPC patterning system and the coarse-grained model.(A) VPC differentiation. (B) Coarse-grained modeling of VPC patterning. The two-node model with 10 links numbered from 1 to 10 is shown in the left panel. Dashed lines represent intercellular interactions and solid lines intracellular interactions. The modeling system of five Pn.p cells along with their initial and target values is shown in the upper-right panel. The ODE functions of two examples are shown in the lower-right panel.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482679&req=5

pone.0131397.g001: The C. elegans VPC patterning system and the coarse-grained model.(A) VPC differentiation. (B) Coarse-grained modeling of VPC patterning. The two-node model with 10 links numbered from 1 to 10 is shown in the left panel. Dashed lines represent intercellular interactions and solid lines intracellular interactions. The modeling system of five Pn.p cells along with their initial and target values is shown in the upper-right panel. The ODE functions of two examples are shown in the lower-right panel.
Mentions: Vulval development in C. elegans has served as a paradigm for cell fate determination [10,11]. The nematode’s vulva is formed from the descendants of six multipotent VPCs, named P3.p to P8.p, that adopt one of three cell fates (Fig 1A). Early evidence showed that their fates depend on their distances to an anchor cell (AC), which is near the VPCs and secretes an epidermal growth factor (EGF) signal [11,12]. The VPC closest to the AC (P6.p) becomes a primary (1°) cell; the VPCs at an intermediate distance (P5.p and P7.p) become secondary (2°) cells; and the more distant ones (P3.p, P4.p and P8.p) become tertiary (3°) cells (Fig 1A). Two important pathways have been uncovered that contribute to the VPC patterning: the inductive signal pathway and the lateral signal pathway [11,13–16]. More specifically, the inductive signal is transduced by the receptor-tyrosine kinase (RTK) pathway with diffusible EGF from the AC as its ligand. The lateral signal is transduced by the Notch pathway between the VPCs themselves, with Notch as its receptor. The ligands of the Notch pathway have two forms: diffusible DSL-1 and membrane-bound LAG-2 and APX-1 [17]. Evidence showed that the two pathways and their crosstalk induce VPC patterning [18].

Bottom Line: We show that the topology derived by mapping currently known biochemical pathways to our model matches one of our identified functional topologies.Furthermore, our robustness analysis predicts a possible missing link related to the lateral antagonism strategy.Overall, we provide a theoretical atlas of all possible functional networks in varying environments, which may guide novel discoveries of the biological interactions in vulval development of Caenorhabditis elegans and related species.

View Article: PubMed Central - PubMed

Affiliation: Center for Quantitative Biology and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.

ABSTRACT
The vulval precursor cell (VPC) fate patterning in Caenorhabditis elegans is a classic model experimental system for cell fate determination and patterning in development. Despite its apparent simplicity (six neighboring cells arranged in one dimension) and many experimental and computational efforts, the patterning strategy and mechanism remain controversial due to incomplete knowledge of the complex biology. Here, we carry out a comprehensive computational analysis and obtain a reservoir of all possible network topologies that are capable of VPC fate patterning under the simulation of various biological environments and regulatory rules. We identify three patterning strategies: sequential induction, morphogen gradient and lateral antagonism, depending on the features of the signal secreted from the anchor cell. The strategy of lateral antagonism, which has not been reported in previous studies of VPC patterning, employs a mutual inhibition of the 2° cell fate in neighboring cells. Robust topologies are built upon minimal topologies with basic patterning strategies and have more flexible and redundant implementations of modular functions. By simulated mutation, we find that all three strategies can reproduce experimental error patterns of mutants. We show that the topology derived by mapping currently known biochemical pathways to our model matches one of our identified functional topologies. Furthermore, our robustness analysis predicts a possible missing link related to the lateral antagonism strategy. Overall, we provide a theoretical atlas of all possible functional networks in varying environments, which may guide novel discoveries of the biological interactions in vulval development of Caenorhabditis elegans and related species.

No MeSH data available.