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Simulation-based model checking approach to cell fate specification during Caenorhabditis elegans vulval development by hybrid functional Petri net with extension.

Li C, Nagasaki M, Ueno K, Miyano S - BMC Syst Biol (2009)

Bottom Line: In particular, an evaluation was successfully done by using our VPC fate model to investigate one target derived from biological experiments involving hybrid lineage observations.More insights are also suggested.The quantitative simulation-based model checking approach is a useful means to provide us valuable biological insights and better understandings of biological systems and observation data that may be hard to capture with the qualitative one.

View Article: PubMed Central - HTML - PubMed

Affiliation: Human Genome Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. chenli@ims.u-tokyo.ac.jp

ABSTRACT

Background: Model checking approaches were applied to biological pathway validations around 2003. Recently, Fisher et al. have proved the importance of model checking approach by inferring new regulation of signaling crosstalk in C. elegans and confirming the regulation with biological experiments. They took a discrete and state-based approach to explore all possible states of the system underlying vulval precursor cell (VPC) fate specification for desired properties. However, since both discrete and continuous features appear to be an indispensable part of biological processes, it is more appropriate to use quantitative models to capture the dynamics of biological systems. Our key motivation of this paper is to establish a quantitative methodology to model and analyze in silico models incorporating the use of model checking approach.

Results: A novel method of modeling and simulating biological systems with the use of model checking approach is proposed based on hybrid functional Petri net with extension (HFPNe) as the framework dealing with both discrete and continuous events. Firstly, we construct a quantitative VPC fate model with 1761 components by using HFPNe. Secondly, we employ two major biological fate determination rules - Rule I and Rule II - to VPC fate model. We then conduct 10,000 simulations for each of 48 sets of different genotypes, investigate variations of cell fate patterns under each genotype, and validate the two rules by comparing three simulation targets consisting of fate patterns obtained from in silico and in vivo experiments. In particular, an evaluation was successfully done by using our VPC fate model to investigate one target derived from biological experiments involving hybrid lineage observations. However, the understandings of hybrid lineages are hard to make on a discrete model because the hybrid lineage occurs when the system comes close to certain thresholds as discussed by Sternberg and Horvitz in 1986. Our simulation results suggest that: Rule I that cannot be applied with qualitative based model checking, is more reasonable than Rule II owing to the high coverage of predicted fate patterns (except for the genotype of lin-15ko; lin-12ko double mutants). More insights are also suggested.

Conclusion: The quantitative simulation-based model checking approach is a useful means to provide us valuable biological insights and better understandings of biological systems and observation data that may be hard to capture with the qualitative one.

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Related in: MedlinePlus

Schematic representations of VPC fate specification in wild-type hermaphrodites. (a) The anchor cell produces a graded inductive signal and causes six equivalent cells to adopt fates in a precise pattern. (b) The sublineage is generated according to each specified cell fate. The sublineage is a determined pattern of cell divisions which produces a characteristic set of progeny cell types. Sternberg and Horvitz have defined vulval cell types (after two rounds of VPC divisions) by two criteria as follows: the axis of the third round nuclear divisions (L, longitudinal axis; T, transverse axis; N, no division; S is to join the large hypodermal syncytium (hyp7)), and adherence to the ventral cuticle [32].
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Figure 3: Schematic representations of VPC fate specification in wild-type hermaphrodites. (a) The anchor cell produces a graded inductive signal and causes six equivalent cells to adopt fates in a precise pattern. (b) The sublineage is generated according to each specified cell fate. The sublineage is a determined pattern of cell divisions which produces a characteristic set of progeny cell types. Sternberg and Horvitz have defined vulval cell types (after two rounds of VPC divisions) by two criteria as follows: the axis of the third round nuclear divisions (L, longitudinal axis; T, transverse axis; N, no division; S is to join the large hypodermal syncytium (hyp7)), and adherence to the ventral cuticle [32].

Mentions: The C. elegans vulva is an egg-laying organ which is constituted by the descendants of three VPCs. The three VPCs are the members of six initially equivalent VPCs that are consecutively numbered P3.p – P8.p (termed Pn.p cells). In response to extracellular signaling pathways, each VPC has a potential to adopt one of three alternative cell fates (1°, 2°, 3°) (see Figure 3(a)). Six cell fates of Pn.p cells comprise a cell fate pattern in the form of [P3.p P4.p P5.p P6.p P7.p P8.p]. In wild-type worms, P3.p – P8.p always adopt a same pattern of fates (i.e., [332123]). The sublineage is then generated according to each specified VPC fate. The sublineage is a determined pattern of cell divisions which produces a characteristic set of progeny cell types. Figure 3(b) shows the sublineage of respective VPC fate according to the criteria defined by Sternberg and Horvitz [32].


Simulation-based model checking approach to cell fate specification during Caenorhabditis elegans vulval development by hybrid functional Petri net with extension.

Li C, Nagasaki M, Ueno K, Miyano S - BMC Syst Biol (2009)

Schematic representations of VPC fate specification in wild-type hermaphrodites. (a) The anchor cell produces a graded inductive signal and causes six equivalent cells to adopt fates in a precise pattern. (b) The sublineage is generated according to each specified cell fate. The sublineage is a determined pattern of cell divisions which produces a characteristic set of progeny cell types. Sternberg and Horvitz have defined vulval cell types (after two rounds of VPC divisions) by two criteria as follows: the axis of the third round nuclear divisions (L, longitudinal axis; T, transverse axis; N, no division; S is to join the large hypodermal syncytium (hyp7)), and adherence to the ventral cuticle [32].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2691733&req=5

Figure 3: Schematic representations of VPC fate specification in wild-type hermaphrodites. (a) The anchor cell produces a graded inductive signal and causes six equivalent cells to adopt fates in a precise pattern. (b) The sublineage is generated according to each specified cell fate. The sublineage is a determined pattern of cell divisions which produces a characteristic set of progeny cell types. Sternberg and Horvitz have defined vulval cell types (after two rounds of VPC divisions) by two criteria as follows: the axis of the third round nuclear divisions (L, longitudinal axis; T, transverse axis; N, no division; S is to join the large hypodermal syncytium (hyp7)), and adherence to the ventral cuticle [32].
Mentions: The C. elegans vulva is an egg-laying organ which is constituted by the descendants of three VPCs. The three VPCs are the members of six initially equivalent VPCs that are consecutively numbered P3.p – P8.p (termed Pn.p cells). In response to extracellular signaling pathways, each VPC has a potential to adopt one of three alternative cell fates (1°, 2°, 3°) (see Figure 3(a)). Six cell fates of Pn.p cells comprise a cell fate pattern in the form of [P3.p P4.p P5.p P6.p P7.p P8.p]. In wild-type worms, P3.p – P8.p always adopt a same pattern of fates (i.e., [332123]). The sublineage is then generated according to each specified VPC fate. The sublineage is a determined pattern of cell divisions which produces a characteristic set of progeny cell types. Figure 3(b) shows the sublineage of respective VPC fate according to the criteria defined by Sternberg and Horvitz [32].

Bottom Line: In particular, an evaluation was successfully done by using our VPC fate model to investigate one target derived from biological experiments involving hybrid lineage observations.More insights are also suggested.The quantitative simulation-based model checking approach is a useful means to provide us valuable biological insights and better understandings of biological systems and observation data that may be hard to capture with the qualitative one.

View Article: PubMed Central - HTML - PubMed

Affiliation: Human Genome Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. chenli@ims.u-tokyo.ac.jp

ABSTRACT

Background: Model checking approaches were applied to biological pathway validations around 2003. Recently, Fisher et al. have proved the importance of model checking approach by inferring new regulation of signaling crosstalk in C. elegans and confirming the regulation with biological experiments. They took a discrete and state-based approach to explore all possible states of the system underlying vulval precursor cell (VPC) fate specification for desired properties. However, since both discrete and continuous features appear to be an indispensable part of biological processes, it is more appropriate to use quantitative models to capture the dynamics of biological systems. Our key motivation of this paper is to establish a quantitative methodology to model and analyze in silico models incorporating the use of model checking approach.

Results: A novel method of modeling and simulating biological systems with the use of model checking approach is proposed based on hybrid functional Petri net with extension (HFPNe) as the framework dealing with both discrete and continuous events. Firstly, we construct a quantitative VPC fate model with 1761 components by using HFPNe. Secondly, we employ two major biological fate determination rules - Rule I and Rule II - to VPC fate model. We then conduct 10,000 simulations for each of 48 sets of different genotypes, investigate variations of cell fate patterns under each genotype, and validate the two rules by comparing three simulation targets consisting of fate patterns obtained from in silico and in vivo experiments. In particular, an evaluation was successfully done by using our VPC fate model to investigate one target derived from biological experiments involving hybrid lineage observations. However, the understandings of hybrid lineages are hard to make on a discrete model because the hybrid lineage occurs when the system comes close to certain thresholds as discussed by Sternberg and Horvitz in 1986. Our simulation results suggest that: Rule I that cannot be applied with qualitative based model checking, is more reasonable than Rule II owing to the high coverage of predicted fate patterns (except for the genotype of lin-15ko; lin-12ko double mutants). More insights are also suggested.

Conclusion: The quantitative simulation-based model checking approach is a useful means to provide us valuable biological insights and better understandings of biological systems and observation data that may be hard to capture with the qualitative one.

Show MeSH
Related in: MedlinePlus