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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.


Biological network and its mapping to 1P-2P-5P-3N-4N.(A) The key known pathways in VPC patterning. The proteins and pathways in green correspond to the AC node; those in blue correspond to the 1° node; those in red correspond to the 2° node; and gray indicates that they are repressed in that cell. The regulations among different nodes are labeled with the corresponding links in the topology 1P-2P-5P-3N-4N and in different colors. (B) Q values of the topologies that contain 1P-2P-5P-3N-4N. (C) Inferred network constructed based on known links and our inferred link 10N, which is an inhibitory regulation between the 2° nodes of neighboring Pn.p cells. The known links are in gray. (D) Mutant patterns produced by topologies 1P-2P-5P-3N-4N and 1P-2P-5P-3N-4N-10N under AC ablation and EGF overexpression. The top two most-frequent patterns along with their occurrences from total 1,000 runs of simulation are shown. Simulation was modeled with “Combined AND & Additive” rule.
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pone.0131397.g008: Biological network and its mapping to 1P-2P-5P-3N-4N.(A) The key known pathways in VPC patterning. The proteins and pathways in green correspond to the AC node; those in blue correspond to the 1° node; those in red correspond to the 2° node; and gray indicates that they are repressed in that cell. The regulations among different nodes are labeled with the corresponding links in the topology 1P-2P-5P-3N-4N and in different colors. (B) Q values of the topologies that contain 1P-2P-5P-3N-4N. (C) Inferred network constructed based on known links and our inferred link 10N, which is an inhibitory regulation between the 2° nodes of neighboring Pn.p cells. The known links are in gray. (D) Mutant patterns produced by topologies 1P-2P-5P-3N-4N and 1P-2P-5P-3N-4N-10N under AC ablation and EGF overexpression. The top two most-frequent patterns along with their occurrences from total 1,000 runs of simulation are shown. Simulation was modeled with “Combined AND & Additive” rule.

Mentions: We then asked what topology is the closest to the underlying biological network that executes VPC patterning. We searched the literature and mapped the known pathways that have experimental supports to the simplified links in our coarse-grained model (Fig 8A). In the sequential induction model, EGF signaling from the AC induces the 1° fate in the 1° cell through the Ras-MAPK pathway, and then MAPK promotes Delta-Notch lateral signaling among Pn.p cells to specify 2° fates in 2° cells [14,28]. As a support to the morphogen-based model, the 2° fate in the 2° cells have also been found to be induced by EGF signaling through the RGL-1-RAL-1 pathway [22]. In addition, the negative regulatory roles in the crosstalk between the MAPK and Notch pathways have been found in VPC pattern formation [18,29]. To map these pathways to our 2-node model, MAPK and the downstream pathways are represented by the 1° node, while Ral, Notch and their downstream pathways are represented by the 2° node. Thus, we recovered the topology 1P-2P-5P-3N-4N by mapping the regulatory links among these nodes (Fig 8A). Previous experiments have shown that VPCs lacking let-23 or other components of the Ras-MAPK pathway can specify the 2° fate, as long as they are adjacent to a 1° VPC [19], which means that the specification of 2° fate can be induced by 5P without 2P. On the other hand, evidences also show that an isolated VPC can adopt a 2° fate if exposed to an intermediate LIN-3 concentration [12], which implies that the induction of 2° fate can be induced by 2P independent of 5P. In addition, Zand et al. reported that RAL-1 is sufficient to promote Notch pathway activity and RAL-1 cooperates with Notch to specify 2° fate [22], which suggests 2P is sufficient to specify 2° cell fate. Since 2P and 5P are both sufficient for 2° fate specification, we examined the Q value of this topology with the “Combined AND and Additive” rule. The Q values of the topology 1P-2P-5P-3N-4N for S2 ≤ 0.1 are all >0.1.


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

Ping X, Tang C - PLoS ONE (2015)

Biological network and its mapping to 1P-2P-5P-3N-4N.(A) The key known pathways in VPC patterning. The proteins and pathways in green correspond to the AC node; those in blue correspond to the 1° node; those in red correspond to the 2° node; and gray indicates that they are repressed in that cell. The regulations among different nodes are labeled with the corresponding links in the topology 1P-2P-5P-3N-4N and in different colors. (B) Q values of the topologies that contain 1P-2P-5P-3N-4N. (C) Inferred network constructed based on known links and our inferred link 10N, which is an inhibitory regulation between the 2° nodes of neighboring Pn.p cells. The known links are in gray. (D) Mutant patterns produced by topologies 1P-2P-5P-3N-4N and 1P-2P-5P-3N-4N-10N under AC ablation and EGF overexpression. The top two most-frequent patterns along with their occurrences from total 1,000 runs of simulation are shown. Simulation was modeled with “Combined AND & Additive” rule.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131397.g008: Biological network and its mapping to 1P-2P-5P-3N-4N.(A) The key known pathways in VPC patterning. The proteins and pathways in green correspond to the AC node; those in blue correspond to the 1° node; those in red correspond to the 2° node; and gray indicates that they are repressed in that cell. The regulations among different nodes are labeled with the corresponding links in the topology 1P-2P-5P-3N-4N and in different colors. (B) Q values of the topologies that contain 1P-2P-5P-3N-4N. (C) Inferred network constructed based on known links and our inferred link 10N, which is an inhibitory regulation between the 2° nodes of neighboring Pn.p cells. The known links are in gray. (D) Mutant patterns produced by topologies 1P-2P-5P-3N-4N and 1P-2P-5P-3N-4N-10N under AC ablation and EGF overexpression. The top two most-frequent patterns along with their occurrences from total 1,000 runs of simulation are shown. Simulation was modeled with “Combined AND & Additive” rule.
Mentions: We then asked what topology is the closest to the underlying biological network that executes VPC patterning. We searched the literature and mapped the known pathways that have experimental supports to the simplified links in our coarse-grained model (Fig 8A). In the sequential induction model, EGF signaling from the AC induces the 1° fate in the 1° cell through the Ras-MAPK pathway, and then MAPK promotes Delta-Notch lateral signaling among Pn.p cells to specify 2° fates in 2° cells [14,28]. As a support to the morphogen-based model, the 2° fate in the 2° cells have also been found to be induced by EGF signaling through the RGL-1-RAL-1 pathway [22]. In addition, the negative regulatory roles in the crosstalk between the MAPK and Notch pathways have been found in VPC pattern formation [18,29]. To map these pathways to our 2-node model, MAPK and the downstream pathways are represented by the 1° node, while Ral, Notch and their downstream pathways are represented by the 2° node. Thus, we recovered the topology 1P-2P-5P-3N-4N by mapping the regulatory links among these nodes (Fig 8A). Previous experiments have shown that VPCs lacking let-23 or other components of the Ras-MAPK pathway can specify the 2° fate, as long as they are adjacent to a 1° VPC [19], which means that the specification of 2° fate can be induced by 5P without 2P. On the other hand, evidences also show that an isolated VPC can adopt a 2° fate if exposed to an intermediate LIN-3 concentration [12], which implies that the induction of 2° fate can be induced by 2P independent of 5P. In addition, Zand et al. reported that RAL-1 is sufficient to promote Notch pathway activity and RAL-1 cooperates with Notch to specify 2° fate [22], which suggests 2P is sufficient to specify 2° cell fate. Since 2P and 5P are both sufficient for 2° fate specification, we examined the Q value of this topology with the “Combined AND and Additive” rule. The Q values of the topology 1P-2P-5P-3N-4N for S2 ≤ 0.1 are all >0.1.

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.