Limits...
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.


Different strategies to achieve the pattern.Sequential induction strategy (A), morphogen gradient strategy (B), and lateral antagonism strategy (C) are shown. These strategies are common with both “AND” and “Combined AND & Additive” rules. For each strategy, a simple description of the strategy, representative topology, and the S2 level are listed in the table. Below the table shows the mechanism of representative topology: on the left is a sketch of the topology; in the middle is the graph that shows the regulation among the AC, 1°, and 2° nodes in the 1° (middle) and 2° cells (two sides), where the heavy full lines indicate acting or strong regulation and fine dashed lines indicate no or weak regulation; on the right draws the dynamical value of each node in the 1° cell and 2° cells with increasing time.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4482679&req=5

pone.0131397.g004: Different strategies to achieve the pattern.Sequential induction strategy (A), morphogen gradient strategy (B), and lateral antagonism strategy (C) are shown. These strategies are common with both “AND” and “Combined AND & Additive” rules. For each strategy, a simple description of the strategy, representative topology, and the S2 level are listed in the table. Below the table shows the mechanism of representative topology: on the left is a sketch of the topology; in the middle is the graph that shows the regulation among the AC, 1°, and 2° nodes in the 1° (middle) and 2° cells (two sides), where the heavy full lines indicate acting or strong regulation and fine dashed lines indicate no or weak regulation; on the right draws the dynamical value of each node in the 1° cell and 2° cells with increasing time.

Mentions: In order to investigate how these minimal topologies achieve the function, for each topology we looked into the dynamics of each fate in each cell during the simulation. All of the minimal topologies are found to follow the three strategies illustrated in Fig 4 and described below. The first strategy is adopted for low to medium S2 and employs sequential induction with the motif 1P-5P, in which AC induces 1° fate in its nearest 1° cell which in turn induces 2° fate in the two neighboring 2° cells. Negative links function to repress the 2° fate in 1° cell or 1° fate in 2° cells if necessary, such as 1P-5P-2N-4N (Fig 4A). The second strategy, which is employed by 1P-2P-3N, agrees with the morphogen gradient model, in which 1° and 2° cells read the AC signal directly and make their fate choices according to the signal strength they receive, and only functions at the medium S2 levels (Fig 4B). At first, both 1° and 2° fates are induced in the 1° cell, but only 2° fate is induced in the 2° cells, which is ensured by special constraints of parameter sets (see S1 Text). Then the activated 1° fate further represses 2° fate in the 1° cell. The third strategy, employed by 1P-2P-4N-10N for medium to high S2 levels, works as follows (Fig 4C): first, both 1° and 2° fates are induced in both 1° and 2° cells, then the 2° fate in 1° and 2° cells competes to inhibit each other (10N). In this competition, the 2° fate in the 2° cells wins, and the 2° fate in the 1° cell is inhibited. Consequently, 1° fate in the 2° cells is also inhibited (4N). This strategy, which we name it as “lateral antagonism”, is distinct from the morphogen gradient strategy described above, although they both contain module 1P-2P. The lateral antagonism strategy mainly depends on the competition or mutual inhibition of 2° fate in neighboring cells, while the morphogen gradient strategy mainly depends on the graded signaling from the source cell. We also found a strategy only used for “AND” rule by 1P-2P-3N-6P. In this topology, there are two positive regulatory links on the 1° fate, from AC and the 2° fate of the neighboring cells, which cause different behaviors between the two rules. For the “AND” rule, the activation of the 1° fate needs not only positive regulation from the AC (1P) but also the intercellular positive regulation from the 2° fate (6P), which makes this strategy available with the “AND” rule, exclusively (S2 Fig). In this strategy, 2° fate is induced first in both 1° and 2° cells, then 1° fate is only induced in the 1° cell, and then 2° fate in the 1° cell is repressed.


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

Ping X, Tang C - PLoS ONE (2015)

Different strategies to achieve the pattern.Sequential induction strategy (A), morphogen gradient strategy (B), and lateral antagonism strategy (C) are shown. These strategies are common with both “AND” and “Combined AND & Additive” rules. For each strategy, a simple description of the strategy, representative topology, and the S2 level are listed in the table. Below the table shows the mechanism of representative topology: on the left is a sketch of the topology; in the middle is the graph that shows the regulation among the AC, 1°, and 2° nodes in the 1° (middle) and 2° cells (two sides), where the heavy full lines indicate acting or strong regulation and fine dashed lines indicate no or weak regulation; on the right draws the dynamical value of each node in the 1° cell and 2° cells with increasing time.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131397.g004: Different strategies to achieve the pattern.Sequential induction strategy (A), morphogen gradient strategy (B), and lateral antagonism strategy (C) are shown. These strategies are common with both “AND” and “Combined AND & Additive” rules. For each strategy, a simple description of the strategy, representative topology, and the S2 level are listed in the table. Below the table shows the mechanism of representative topology: on the left is a sketch of the topology; in the middle is the graph that shows the regulation among the AC, 1°, and 2° nodes in the 1° (middle) and 2° cells (two sides), where the heavy full lines indicate acting or strong regulation and fine dashed lines indicate no or weak regulation; on the right draws the dynamical value of each node in the 1° cell and 2° cells with increasing time.
Mentions: In order to investigate how these minimal topologies achieve the function, for each topology we looked into the dynamics of each fate in each cell during the simulation. All of the minimal topologies are found to follow the three strategies illustrated in Fig 4 and described below. The first strategy is adopted for low to medium S2 and employs sequential induction with the motif 1P-5P, in which AC induces 1° fate in its nearest 1° cell which in turn induces 2° fate in the two neighboring 2° cells. Negative links function to repress the 2° fate in 1° cell or 1° fate in 2° cells if necessary, such as 1P-5P-2N-4N (Fig 4A). The second strategy, which is employed by 1P-2P-3N, agrees with the morphogen gradient model, in which 1° and 2° cells read the AC signal directly and make their fate choices according to the signal strength they receive, and only functions at the medium S2 levels (Fig 4B). At first, both 1° and 2° fates are induced in the 1° cell, but only 2° fate is induced in the 2° cells, which is ensured by special constraints of parameter sets (see S1 Text). Then the activated 1° fate further represses 2° fate in the 1° cell. The third strategy, employed by 1P-2P-4N-10N for medium to high S2 levels, works as follows (Fig 4C): first, both 1° and 2° fates are induced in both 1° and 2° cells, then the 2° fate in 1° and 2° cells competes to inhibit each other (10N). In this competition, the 2° fate in the 2° cells wins, and the 2° fate in the 1° cell is inhibited. Consequently, 1° fate in the 2° cells is also inhibited (4N). This strategy, which we name it as “lateral antagonism”, is distinct from the morphogen gradient strategy described above, although they both contain module 1P-2P. The lateral antagonism strategy mainly depends on the competition or mutual inhibition of 2° fate in neighboring cells, while the morphogen gradient strategy mainly depends on the graded signaling from the source cell. We also found a strategy only used for “AND” rule by 1P-2P-3N-6P. In this topology, there are two positive regulatory links on the 1° fate, from AC and the 2° fate of the neighboring cells, which cause different behaviors between the two rules. For the “AND” rule, the activation of the 1° fate needs not only positive regulation from the AC (1P) but also the intercellular positive regulation from the 2° fate (6P), which makes this strategy available with the “AND” rule, exclusively (S2 Fig). In this strategy, 2° fate is induced first in both 1° and 2° cells, then 1° fate is only induced in the 1° cell, and then 2° fate in the 1° cell is repressed.

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.