Predictive Modeling of Signaling Crosstalk

Predictive Modeling of Signaling Crosstalk...

Model execution and model checking can be used to testa biological hypothesis

The model is an explanation of a biological mechanism and its agreement with experimental results is used toeither validate that explanation or state that the model needs adjustment

Mechanistic models are particularly well-suited for capturing the level of understanding obtained using thetools and approaches common in the field of developmentalgenetics and those models are beneficial.


C. elegans vulva – the vulva of a roundworm. Shares cellular and molecular structures and control pathways with higher organisms. Developmental process is complex and may provide insight into complex organ development.


Anchor Cell (AC) – in the worm gonadVulva Precursor Cell (VPC) – identity given as PX.p (X∈{3,4,5,6,7,8}) – string of functionally equivalent cells (initially) along the ventral body wall


vulva formation – cells function in three different ways: 1o - stack to form the vulva 2o - supporting cells to open and close the vulva 3o - fuse with the skin of the worm

Functions are not predetermined but they n. always happenthe same way!! Move the AC to get a new vulva position!!


The signaling –


The signaling – The anchor cell starts the ball rolling with an induction signal (instruction to take up a function) to some VPC. A strong signal activates the Vul signal transduction pathway which then


The signaling – The anchor cell starts the ball rolling with an induction signal (instruction to take up a function) to some VPC. A strong signal activates the Vul signal transduction pathway which then turns on the 1o gene and turns off the 3o gene.


The signaling – The anchor cell starts the ball rolling with an induction signal (instruction to take up a function) to some VPC. A strong signal activates the Vul signal transduction pathway which then turns on the 1o gene and turns off the 3o gene. The Muv signal is trying to turn off the Vul signal but it can't do it – too weak.


The signaling – The 1o cell tells its neighbors NOT to become 1o cells through a Lateral Signal (LS) pathway.


The signaling – The 1o cell tells its neighbors NOT to become 1o cells through a Lateral Signal (LS) pathway and turns off its own receptor of LS so that it does not prevent itself from not becoming a 1o cell and does not listen to attempts from neighbors to stop it.


Details – the AC chooses three cells and sends inductionsignals, the strongest going to P6.p (usually). These haveprogeny – 22 in all. The lateral signal from P6.p to itsneighbors causes them to take a 2o fate.

synMuv genes prevent the hypodermal layer from generatinglateral signals.

The pattern is always 3o-3o-2o-1o-2o-3o


Organizer – sets up initializationScheduler – handles synchronization between VPCsVPC – runs own copy of program, depends on inputs from neighbors, all initialized the same way


Model for signaling – activation by low IS is slower than medium IS is slower than high IS.


VPC module – main – follows progression toward fate assumption – ends at 1,2,3 – 4 time delay steps to get there lin-12 – lateral signal pathway – time delays for medium


Circuit modeling regulation of egl-17 –


Model Validation –

Set the type of mutation to be studied Choose how to schedule the VPC processes Once cells assume fates, compare with experimental results

Resulting model is highly non-deterministic In one round of cell changes many schedules are possible 4000 ways to complete a round

1036 possible executions 48 different initial states 92000 possible legal assignments to variables (states)

Formal Verification – to ensure that all possible executions from a given mutation match the experimental results.

Verification of model against formalization of experimental results (e.g. that end pattern is 3o-3o-2o-1o-2o-3o)

Then use simulations to predict the outcome of possible exps.


Left timeline starts with high inductive signal, right withmedium inductive signal

AC is absent, IS at equal levels. Execution 1 – tightly

coupled cells both take on role of 1o. Execution 2 – left cellsends its LS slightly before its neighbor. Execution 3 - right cell sends LS slightly before its neighbor.


Model Checking –

1. To show that the devised model will always give results that match what has been observed from experiments in different mutant backgrounds.

2. To query the model. For example, which mutation leads to a stable or unstable fate pattern – if unstable fate pattern is found, the part of the execution that allows it is determined.

This Paper - The model was model checked and two predictions were made based on the result. These were verified experimentally

Predictive Modeling of Signaling Crosstalk

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