Cell-Cell Commun. Macroscopic PDE Mesoscopic Langevin Microscopic Master Eq. Coarse-graining...
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Transcript of Cell-Cell Commun. Macroscopic PDE Mesoscopic Langevin Microscopic Master Eq. Coarse-graining...
Cell-Cell Commun.
Macroscopic PDE
Mesoscopic Langevin
Microscopic Master Eq.
Coarse-graining
Suitable Mathematical Languages for hierarchical System
Single Cell
Development
Scale
DNA
ProteinRNA
Real-World Modeling on Hierarchical Dynamics of Living Matter
K. Yoshikawa, Kyoto Univ. 吉川研一(京大・理・物理)
Current Hypothesis on Morphogenesis:
Turing Pattern (1952)
Reaction Diffusion System
u:activator, v :inhibitor
Necessary Condition
Somitogenesis
Traveling Waves Lead to Stationary Periodic Structure
Masamizu, Kageyama, KY, et al., PNAS 2006
Spatio temporal Pattern
Phase difference among the single cells
Traveling waves of Gene expression (Hes1 / Hes7) move across the presomitic mesoderm (PSM).
Scheme
HeadTail
Time Time
Tail Head
Y. Saga, H. Takeda Nature Reviews 2, 835, (2001).
Head Tail
Cell Cell
Level of Fgf
Cell-Cell Coupling with Activator
Spatial Gradient of Morphogen
・ Total number of lateral train of the cells: ca.50 R ~ 10 mm / each cell
・ Diffusion “inside” a cell is quite fast.
Total Length of the System(PSM)
The system is regarded as the connection of discrete cells
f, g: local kinetics of u, v
Model with Activator Coupling
u:activator,
t1,t2: timescales of local (intra cellular) kinetics
v:inhibitor,
“Turing Pattern” never occurs.
Laplace Operator; From continuous into Discrete
• g changes the local behavior. (Oscillatory to Bistable)
Numerical Settings
t 1 =0.58, t2=3.2×10, D=1.19×10-5, α =0.4, b=0.33, k=1.0, a=1.0, b=1.0.
Fitzhugh-Nagumo type
Dx =0.01, Dt=0.001
Parameterization
Nagahara, Kageyama, KY, etc “Phys. Rev. E, 80, (2009).
g has spatial gradient: g(x)=0.21-0.20x
space
u,
v gu, v, g
Fgf gradient
Head
Tail
Propagation Failure
• Parameter γ is taken as follows:
t , x x t
3.0 2.5 x 4.6 10 4 tspace
tim
e
Emergence of Stationary Pattern on a Growing Embryo
Assumption of linear growth
・Discrete medium:
・ Continuous medium:
stationary pattern may appear.
(Propagation failure in Bistable medium)
is small enough,
i.e.
If
,
Why does propagation fail?
min11
ca.5mm
ca.1mm/min
• Through Galilei Transform, the growth of the embryo is equivalent to the directional flow.
cf; M. Kaern et. al., Faraday Discuss 120, 295, (2002).
Mathematical Equivalence between the growth and directional flow
• Discrete medium• Stationary but vividly
dependent on past history and boundary.
Continuous medium Stationary pattern
independent on past history and boundary.
Present scenario Turing scenario
de Kepper, et al., Science 2009
Difference from the Turing model
Schibler, Current Opinion in Biology, 2005
E. S. Maywood et al , Current Biology, 2006
Circadian Clock: Regulator of daily rhythm “Internal Body Clock”: SCN
(suprachiasmatic nucleus)
Activator-Inhibitor
Cell-Cell coupling with Activator
Ma and K. Yoshikawa. Phys. Rev. E (2009).
Current Hypothesis: Switching &Rhythm are Caused by Chemical Network
Hypothesis of Jacob & Monod
Who manages the expression of 20,000 genes?
Noise in a Single CellNumber Fluctuation Typical Number of Regulatory factors may be on
the order of 101.Temporal Fluctuation Breakdown of Detailed Balance, Occurrence of
Flow and Rhythm in State SpaceSpatial Fluctuation Inhomogenity within Intracellular Space
Is there any other scinario to cause the reduction of freedom in complicated noisy system?
JCP,102,6595(’95); PRL, 76,3029(’96); JPCB, 101, 9396 (‘97).
On/Off Switching of Conformation on a Giant DNA Demonstrated by
Fluorescence Microscopic Observation.
T4 DNA
166kbp; L = 57mm
elongateddensity
Free Energy
5mm
PRL, 76,3029(’96); JPCB, 101, 9396 (‘97).
110~n
Always Continuous
210~n
First-Order Phase Transition
Liquid Solid
Cf: Ar-Cluster, H2O-cluster
N=100 corresponds to DNA with 30kbp, where Kuhn length is 100nm (300bp)
Luckel, Tsumoto, et al., Biophys. Chem.(2003).
Compaction of giant DNA completely inhibits the transcriptional activity
l-ZAP II L-ZAP II
RNA Transcripts on Individual DNA in Micro-SphereTsuji, KY, JACS(2010).
+ Mg2+
Outer Environment
Metabolic Network
Loose PackingIntra-cellular Network
Genetic Regulators
Expression
Transcription
Nuclear Environment
Folder of genes
Tight Packing
Unfolded DNA
Network: Fluctuating pairs of key-locks
Environment: Robust owe to large number
Life is a hybrid system between network and environment.
Lot of Thanks• Thank to all of the
colleagues at Kyoto Univ. and collaborators:
Especially, Dr. Nagahara
Dr. Ma
Prof. Kageyama
Dr. Marcel Hoerning
Welcome to Kyoto
謝謝