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Sven Bergmann Department of Medical Genetics – UNIL & Swiss Institute of Bioinformatics

MSc GBE Course: Genes: from sequence to function Brief Introduction to Systems Biology Sven Bergmann Department of Medical Genetics University of Lausanne Rue de Bugnon 27 - DGM 328  CH-1005 Lausanne  Switzerland work: ++41-21-692-5452 cell: ++41-78-663-4980 http://serverdgm.unil.ch/bergmann.

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Sven Bergmann Department of Medical Genetics – UNIL & Swiss Institute of Bioinformatics

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  1. MSc GBE Course: Genes: from sequence to functionBrief Introduction to Systems BiologySven BergmannDepartment of Medical GeneticsUniversity of LausanneRue de Bugnon 27 - DGM 328 CH-1005 Lausanne Switzerlandwork: ++41-21-692-5452cell: ++41-78-663-4980 http://serverdgm.unil.ch/bergmann

  2. Modeling Crash course Pre-Steady-State Decoding of the Bicoid Morphogen Gradient Sven Bergmann Department of Medical Genetics – UNIL & Swiss Institute of Bioinformatics

  3. PLoS Biology 5(2) e46, 2007

  4. Drosophila as model for Development

  5. Normal Conditions Environmental Changes (Some) Genetic Changes Development is a precise process

  6. How to ensure buffering when patterning proceeds rapidly? Genetic buffering mechanisms are hard to establish in fast development!

  7. The Life Cycle of Drosophila

  8. Drosophila development Maternal bicoid mRNA is localized at anterior pole Diffusion of the bicoid protein establishes gradient (defining anterior-posterior axis) Cascade of gene regulation refines segments of bodyplan (that will determine shape of adult fly)

  9. Free diffusionof developmentally important factors between the nuclei of the syncytium! Syncytial Blastoderm Stage Nuclei divide, but no intercellular membranes yet

  10. diffusion source Morphogen gradient C1 C2 C3 fate 1 fate 2 fate 3 fate 4 Morphogen Gradients are used for translating cellular position into cell-fate Cell fates are determined according to the concentration of the morphogen

  11. bcd hb gt Kr The maternal and zygotic segmentation genes form a hierarchical network of sequential transcriptional regulation Maternal genes: Bicoid (bcd) Caudal (cad) Zygotic genes: Hunchback (hb) Giant (gt) Kruppel (Kr) Knirps (kni) …

  12. What happens when perturbing the system?

  13. Changes in bicoid mRNA dosage lead to shifts in expression domain of downstream genes:

  14. Quantitative Study using Automated Image Processing a: mark anterior and posterior pole, first and last eve-stripe b: extract region around dorsal midlinec: semi-automatic determination of stripes/boundaries

  15. Our Experimental Results:

  16. Shifts are small and position-dependent!

  17. Change in concentration of the morphogen at position x, time t Degradationα: decay rate Source Diffusion D: diffusion const. A bit of Theory… The morphogen density M(x,t) can be modeled by a differential equation (reaction diffusion equation):

  18. The Canonical Model Steady state: (no change in time) Solution: M(x) Length scale: x decay time

  19. Original gradient Gradient for half production rate In steady-state induced shifts are independent of position:

  20. What if the profile has not reached its steady state yet? Steady state assumption is ad-hoc Early patterning processes are very rapid Consistent with typical values for diffusion

  21. Modeling the morphogen (Bcd) by a time-dependent PDE:

  22. Shifts induced by altered bcd dosage: steady-state vs transient profile Decoding the transient profile: • Position-dependent shifts • Smaller shifts towards the posterior pole

  23. Model vs Data Prediction: Bcd diffusion is relatively small!

  24. Pattern Fixation hb gt Kr Can mutual suppression of gap genes fixate their expression domains after initial pattern is established?

  25. Change in concentration of gene i=Bcd, Gt, Hb, … at position x, time t Degradationαi: decay rate Source Diffusion Di: diffusion const. Simulating the system Model using partial differential equations:

  26. Start at time ti Sum over activators: OR Multiply suppressors: AND h(y) n>0 1 Hill-function: ½ n<0 y= Source term encodes gene-interactions

  27. Gradient evolution in time

  28. Simulations agreewith naïve model

  29. Buffering is lost when patterning occurs after Bcd has reachedsteady state (tinit >> τ)!

  30. position lacZ Kni Kr Gt Bcd Kni Bcd activator repressors time “Nail down” experiment position Kni Kr Gt Bcd Kni Bcd activator repressors time lacZ

  31. lacZ reporter indicates that Bcd has not reached steady state during patterning

  32. Conclusion: Systems approach to the gap-gene network reveals that dynamic decoding of pre-steady state morphogen gradient is consistent with experimental data from the anterior-posterior patterning in early Drosophila embryos

  33. Acknowledgements Sven Bergmann, Oded Sandler, Hila Sberro, Sara Shnider, Ben-Zion Shilo, Eyal Schejter and Naama Barkai PLoS Biology 5(2): e46 Collaboration with Profs. Naama Barkai & Benny Shilo, Weizmann Institute of Science

  34. Gregor et al., 2007

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