Gene Regulation Networks with Signaling and Cell Division in Developmental Simulations

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Gene Regulation Networks with Signaling and
Cell Division in Developmental Simulations
Eric Mjolsness(1,3), Bruce Shapiro(2), Victoria
Gor(2), Henrik Jönsson(1,4)
(1)Division of Biology and (2)Jet Propulsion
Laboratory, California Institute of Technology,
Pasadena, CA
(3)Information and Computer Science, University
of California, Irvine, CA
(4)Complex Systems Division, Lund University,
Lund, Sweden
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Outline

• Biological Target Shoot Apical Meristem
• Model Description (brief)
• Simulation 1 Growing 2D Toy Meristem
• Simulation 2 Static 3D SAM Gene Network

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Arabidopsis thaliana

• Genome sequenced (25000 genes)
• Large number of offsprings
• Short generation time
• Small size

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Shoot Apical Meristem SAM

• Source of the aboveground plant
• Small ( 1000 cells)
• Cytologically defined regions (and layers)
• Known gene expression regions

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SAM Important WT Gene Expressions
Brand et. al., Science 289, 617-619, (2000)
wus
Fletcher et al., Science 283, 1911-1914, (1999)
clv3 (small, extracellular)
clv1 (receptor kinase)
wus (homeodomain, transcription factor)
List is longer stm, atml1, ufo, ...
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SAM Loss of Function Mutations

• clv (Fig. B and D) enlarged meristem
• enlarged expression domain for clv1,3 and wus
• wus arrested meristems
• loss of or decreased clv3 expression
• Brand et. al., Plant Physiology 129, 565-575,
  (2002)
• wus and clv comparable to wus single mutants
• Schoof et. al., Cell 100, 635-644, (2000)

clv3 expression in clv1 mutants
Fletcher et al., Science 283, 1911-1914, (1999)
Brand et. al., Science 289, 617-619, (2000)
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SAM Experimental Suggestions

• wus induce clv1/3 expression
• clv1/3 network inhibit wus expression

clv3 marks stem cells and wus defines an
"organizing center"
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Model Description

• Spherical cells, radial growth
• Mechanical interaction, truncated spring
  potential
• Cell cycle/division models
• Protein/resource concentrations within cells

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Protein regulation model
Internal
External
Receptor, c - Ligand, b
Mjolsness et al., J. Theor. Biol. 152, 429-453
(1991)
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Simulation 1 Toy Meristem in 2D Plant
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Toy Meristem Result
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Toy Meristem Statistics
t 5000
t 10000
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Simulation 2 "Real" Gene Network in 3D

• No growth
• wus expression domain as initial condition
• No repression from clv1/3 network

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SAM Gene Network Model
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SAM Gene Network Results
protein concentrations
wus(init) and L1
X
Y
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SAM Gene Network Results Cont.
clv3 expression
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Gene Network Simulation Comments

• Parameters tuned by hand (no data)
• No growth
• Hypotheses introduced
• Few initial conditions
• "Correct" expression domains

??
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Future Work

• Test L1 hypothesis with ATML1 experiments
• New competing hypotheses (clv3, ...)
• Add growth and clv1/3 repression on wus
  (problems!)
• Combine Cellerator with C/C code
• Model other systems

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Conclusions

• Modeling framework for multicellular simulations
• Simulations of SAM in Arabidopsis thaliana
• Systems Biology approach within reach?
• still much to do!

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Acknowledgements

• Collaborators
• Eric Mjolsness, Bruce Shapiro and Victoria Gor
• Barbara Wold, Elliot Meyerowitz, Marcus Heisler
  and Venugopala Reddy (Division of Biology,
  Caltech)
• Financial support

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PromoterGene Mutations

• clv1 wus
• similar to clv mutants
• Schoof et. al., Cell 100, 635-644, (2000)
• clv3wus
• enlarged "meristem
• clv3 and wus expression in outer layer cells
• Brand et. al., Plant Physiology 129, 565-575,
  (2002)

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Grn-equation, example
X
Y
Z
Defines a line in X,Y space
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SAM, Experimental Suggestions
wus induce clv1/3 expression
clv1/3 network inhibit wus expression
clv3 marks stem cells and wus defines an
"organizing center"
clv3
clv1
wus