Modeling Heterocyst Pattern Formation in Cyanobacteria

Ziomara P. Gerdtzen, J. Cristian Salgado, Axel Osses, Juan Asenjo, Ivan Rapaport and Barbara Andrews
RIB2008 Pontificia Universidad Catolica October 15, 2008

Millennium Institute for Cell Dynamics and Biotechnology (ICDB) Department of Chemical Engineering and Biotechnology

University of Chile

Modeling Heterocyst Pattern Formation in Cyanobacteria

(or what happens when you mix mathematicians, biologists and engineers)
Ziomara P. Gerdtzen, J. Cristian Salgado, Axel Osses, Juan Asenjo, Ivan Rapaport and Barbara Andrews
RIB2008 Pontificia Universidad Catolica October 15, 2008

Millennium Institute for Cell Dynamics and Biotechnology (ICDB) Department of Chemical Engineering and Biotechnology

University of Chile

A few words about our Institute

The goal of our Institute is to conduct frontier research in cell function and dynamics and to develop models of important biological systems using a modern Systems Biology approach This holistic approach is being conducted by a multidisciplinary team of bioengineers, cell and molecular biologists, mathematicians, biochemists, chemists and computer scientists

Very exciting things are going on here!

Our Institute has 3 main objectives:

The development of novel approaches in the field of Systems Biology that should result in original solutions to more traditional biological problems To have an impact on scientific problems of national as well as international importance

The application of the knowhow existing in the different groups of the Institute to the solution of problems of importance in Chile and abroad (Applied Research)

http://www.icdb.uchile.cl

Cyanobacteria

Aquatic and photosynthetic (blue-green algae) Can form colonies (filaments) Cell types:

Vegetative (photosynthetic) Akinetes (climate-resistant) Heterocysts (nitrogen fixation)

Anabaena catenula

Differentiation to Heterocysts

One of every ten vegetative cells differentiates into nitrogen-fixing heterocyst Triggered by absence of a fixed nitrogen source Genes involved:

NtcA PatS HetR

A: High N B: Low N

Genes Involved in Differentiation

NtcA stimulates HetR expression HetR phosphorylated by PatA Indirect activation of genes for heterocyst development HetR protease, acts on PatS PatS peptide inhibits PatA

The Proposed Model

General model: Coupled NL Differential Equations

NtcA, HetR PatS NtcA, HetR PatS

General model: Coupled NL Differential Equations

NtcA, HetR PatS NtcA, HetR PatS

General model: Coupled NL Differential Equations

NtcA, HetR PatS NtcA, HetR PatS

Simulations: Convergence from Random Initial Conditions

Time

Effect of D

Relationship between diffusion coefficients for PatS and Nitrogen, and the systems behavior

Average Distance vs. Cell Number

The average distance between heterocysts LH in the absence of nitrogen for wild type

Expression Profiles

ntcA Expression vs. Average Distance

Inhibitory action of neighboring cells on ntcA expression is reduced as LH increases Eventually, this expression is high enough to trigger cell differentiation

Effect of Perturbations

The systems response to disturbances on nitrogen levels, knock out of patS and over expression of hetR was studied Results were compared with experimental observations

Effect of Perturbations: Simulation Results

In the presence of nitrogen no differentiation into heterocysts is observed

A: High N

Some cells differentiate into heterocysts in the absence of nitrogen, with an LH ~10 cells

B: Low N Wild type

For patS knockouts the inhibitory effect of PatS is reduced, decreasing LH and allowing the formation of heterocyst clusters

D: Low N Low PatS

HetR over expression leads the formation of heterocyst clusters, with a pattern similar to the one observed for patS knock outs

D: Low N Low PatS

Over expression of hetR leads to the formation of heterocysts under normally repressing conditions

Conclusions

In presence of Nitrogen each cell has only one attractor (vegetative cell) In absence of Nitrogen there are several attractors where some cells differentiate (to heterocyst) The model allows quantification, computation of the differentiation distance as a function of the diffusion coefficient Captures key feature: LH ~10 cells between heterocysts

Conclusions

The model reproduces experimental results for over expression and knock out of patS and hetR Expression profiles are consistent with experimental data No assumptions on the range of action of the differentiation activator HetR and the inhibitor PatS

References

Adams, D.G. (2000). Heterocyst Formation in Cyanobacteria. Current opinion in microbiology 3(6): 618. Golden, J.W. and Yoon, H.S. (2003). Heterocyst Development in Anabaena. Current opinion in microbiology 6(6): 557. Hammel, M. and Prusinkiewicz, P. (1996). Visualization of Developmental Processes by Extrusion in Space-Time. Proceedings of Graphics Interface: 246. Haselkorn, R. (1998). How Cyanobacteria Count to 10. Science (New York, N.Y 282(5390): 891. Yoon, H.S. and Golden, J.W. (1998). Heterocyst Pattern Formation Controlled by a Diffusible Peptide. Science (New York, N.Y 282(5390): 935.

Questions?