Predictive Modeling of Signaling Crosstalk... Model execution and model checking can be used to test a biological hypothesis

Transcription

1 Model execution and model checking can be used to test a biological hypothesis The model is an explanation of a biological mechanism and its agreement with experimental results is used to either validate that explanation or state that the model needs adjustment Mechanistic models are particularly well-suited for capturing the level of understanding obtained using the tools and approaches common in the field of developmental genetics and those models are beneficial.

2 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.

3 Anchor Cell (AC) in the worm gonad Vulva 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

4 vulva formation cells function in three different ways: 1 o - stack to form the vulva 2 o - supporting cells to open and close the vulva 3 o - fuse with the skin of the worm Functions are not predetermined but they n. always happen the same way!! Move the AC to get a new vulva position!!

5 The signaling

6 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

7 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 1 o gene and turns off the 3 o gene.

8 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 1 o gene and turns off the 3 o gene. The Muv signal is trying to turn off the Vul signal but it can't do it too weak.

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

10 The signaling The 1 o cell tells its neighbors NOT to become 1 o 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 1 o cell and does not listen to attempts from neighbors to stop it.

11 Details the AC chooses three cells and sends induction signals, the strongest going to P6.p (usually). These have progeny 22 in all. The lateral signal from P6.p to its neighbors causes them to take a 2 o fate. synmuv genes prevent the hypodermal layer from generating lateral signals. The pattern is always 3 o -3 o -2 o -1 o -2 o -3 o

12 Organizer sets up initialization Scheduler handles synchronization between VPCs VPC runs own copy of program, depends on inputs from neighbors, all initialized the same way

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

14 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

15 Circuit modeling regulation of egl-17

16 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 possible executions 48 different initial states 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 3 o -3 o -2 o -1 o -2 o -3 o ) Then use simulations to predict the outcome of possible exps.

17 Left timeline starts with high inductive signal, right with medium inductive signal AC is absent, IS at equal levels. Execution 1 tightly coupled cells both take on role of 1 o. Execution 2 left cell sends its LS slightly before its neighbor. Execution 3 - right cell sends LS slightly before its neighbor.

18 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