Lutz Brusch

Ligand-Specific c-Fos Expression Emerges from the Spatiotemporal Control of ErbB Network Dynamics

Activation of ErbB receptors by epidermal growth factor (EGF) or heregulin (HRG) determines distinct cell-fate decisions, although signals propagate through shared pathways. Using mathematical modeling and experimental approaches, we unravel how HRG and EGF generate distinct, all-or-none responses of the phosphorylated transcription factor c-Fos. In the cytosol, EGF induces transient and HRG induces sustained ERK activation. In the nucleus, however, ERK activity and c-fos mRNA expression are transient for both ligands. Knockdown of dual-specificity phosphatases extends HRG-stimulated nuclear ERK activation, but not c-fos mRNA expression, implying the existence of a HRG-induced repressor of c-fos transcription. Further experiments confirmed that this repressor is mainly induced by HRG, but not EGF, and requires new protein synthesis. We show how a spatially distributed, signaling-transcription cascade robustly discriminates between transient and sustained ERK activities at the c-Fos system level. The proposed control mechanisms are general and operate in different cell types, stimulated by various ligands.

Membrane identity and GTPase cascades regulated by toggle and cut-out switches

Key cellular functions and developmental processes rely on cascades of GTPases. GTPases of the Rab family provide a molecular ID code to the generation, maintenance and transport of intracellular compartments. Here, we addressed the molecular design principles of endocytosis by focusing on the conversion of early endosomes into late endosomes, which entails replacement of Rab5 by Rab7. We modelled this process as a cascade of functional modules of interacting Rab GTPases. We demonstrate that intermodule interactions share similarities with the toggle switch described for the cell cycle. However, Rab5‐to‐Rab7 conversion is rather based on a newly characterized ‘cut‐out switch’ analogous to an electrical safety‐breaker. Both designs require cooperativity of auto‐activation loops when coupled to a large pool of cytoplasmic proteins. Live cell imaging and endosome tracking provide experimental support to the cut‐out switch in cargo progression and conversion of endosome identity along the degradative pathway. We propose that, by reconciling module performance with progression of activity, the cut‐out switch design could underlie the integration of modules in regulatory cascades from a broad range of biological processes.

Morpheus: a user-friendly modeling environment for multiscale and multicellular systems biology

Summary: Morpheus is a modeling environment for the simulation and integration of cell-based models with ordinary differential equations and reaction-diffusion systems. It allows rapid development of multiscale models in biological terms and mathematical expressions rather than programming code. Its graphical user interface supports the entire workflow from model construction and simulation to visualization, archiving and batch processing. Availability and implementation: Binary packages are available at http://imc.zih.tu-dresden.de/wiki/morpheus for Linux, Mac OSX and MS Windows. Contact: walter.deback@tu-dresden.de Supplementary information: Supplementary data are available at Bioinformatics online.

Dewetting of thin films on heterogeneous substrates: Pinning versus coarsening

We study a model for a thin liquid film dewetting from a periodic heterogeneous substrate (template). The amplitude and periodicity of a striped template heterogeneity necessary to obtain a stable periodic stripe pattern, i.e., pinning, are computed. This requires a stabilization of the longitudinal and transversal modes driving the typical coarsening dynamics during dewetting of a thin film on a homogeneous substrate. If the heterogeneity has a larger spatial period than that of the critical dewetting mode, weak heterogeneities are sufficient for pinning. Our results imply a large region of coexistence between coarsening dynamics and pinning.

Modulated amplitude waves and defect formation in the one-dimensional complex Ginzburg-Landau equation

The transition from phase chaos to defect chaos in the complex Ginzburg–Landau equation (CGLE) is related to saddle-node bifurcations of modulated amplitude waves (MAWs). First, the spatial period P of MAWs is shown to be limited by a maximum PSN which depends on the CGLE coefficients; MAW-like structures with period larger than PSN evolve to defects. Second, slowly evolving near-MAWs with average phase gradients ν ≈ 0 and various periods occur naturally in phase chaotic states of the CGLE. As a measure for these periods, we study the distributions of spacings p between neighbouring peaks of the phase gradient. A systematic comparison of p and PSN as a function of coefficients of the CGLE shows that defects are generated at locations where p becomes larger than PSN. In other words, MAWs with period PSN represent “critical nuclei” for the formation of defects in phase chaos and may trigger the transition to defect chaos. Since rare events where p becomes sufficiently large to lead to defect formation may only occur after a long transient, the coefficients where the transition to defect chaos seems to occur depend on system size and integration time. We conjecture that in the regime where the maximum period PSN has diverged, phase chaos persists in the thermodynamic limit.

Predicting pancreas cell fate decisions and reprogramming with a hierarchical multi-attractor model.

Cell fate reprogramming, such as the generation of insulin-producing β cells from other pancreas cells, can be achieved by external modulation of key transcription factors. However, the known gene regulatory interactions that form a complex network with multiple feedback loops make it increasingly difficult to design the cell reprogramming scheme because the linear regulatory pathways as schemes of causal influences upon cell lineages are inadequate for predicting the effect of transcriptional perturbation. However, sufficient information on regulatory networks is usually not available for detailed formal models. Here we demonstrate that by using the qualitatively described regulatory interactions as the basis for a coarse-grained dynamical ODE (ordinary differential equation) based model, it is possible to recapitulate the observed attractors of the exocrine and β, δ, α endocrine cells and to predict which gene perturbation can result in desired lineage reprogramming. Our model indicates that the constraints imposed by the incompletely elucidated regulatory network architecture suffice to build a predictive model for making informed decisions in choosing the set of transcription factors that need to be modulated for fate reprogramming.

Modulated Amplitude Waves and the Transition from Phase to Defect Chaos

The mechanism for transitions from phase to defect chaos in the one-dimensional complex Ginzburg-Landau equation (CGLE) is presented. We describe periodic coherent structures of the CGLE, called modulated amplitude waves (MAWs). MAWs of various periods P occur in phase chaotic states. A bifurcation study of the MAWs reveals that for sufficiently large period, pairs of MAWs cease to exist via a saddle-node bifurcation. For periods beyond this bifurcation, incoherent near-MAW structures evolve towards defects. This leads to our main result: the transition from phase to defect chaos takes place when the periods of MAWs in phase chaos are driven beyond their saddle-node bifurcation.

On the role of lateral stabilization during early patterning in the pancreas.

The cell fate decision of multi-potent pancreatic progenitor cells between the exocrine and endocrine lineages is regulated by Notch signalling, mediated by cell–cell interactions. However, canonical models of Notch-mediated lateral inhibition cannot explain the scattered spatial distribution of endocrine cells and the cell-type ratio in the developing pancreas. Based on evidence from acinar-to-islet cell transdifferentiation in vitro, we propose that lateral stabilization, i.e. positive feedback between adjacent progenitor cells, acts in parallel with lateral inhibition to regulate pattern formation in the pancreas. A simple mathematical model of transcriptional regulation and cell–cell interaction reveals the existence of multi-stability of spatial patterns whose simultaneous occurrence causes scattering of endocrine cells in the presence of noise. The scattering pattern allows for control of the endocrine-to-exocrine cell-type ratio by modulation of lateral stabilization strength. These theoretical results suggest a previously unrecognized role for lateral stabilization in lineage specification, spatial patterning and cell-type ratio control in organ development.

Nonlinear analysis of the Eckhaus instability: modulated amplitude waves and phase chaos with nonzero average phase gradient

Abstract We analyze the Eckhaus instability of plane waves in the one-dimensional complex Ginzburg–Landau equation (CGLE) and describe the nonlinear effects arising in the Eckhaus unstable regime. Modulated amplitude waves (MAWs) are quasi-periodic solutions of the CGLE that emerge near the Eckhaus instability of plane waves and cease to exist due to saddle-node (SN) bifurcations. These MAWs can be characterized by their average phase gradient ν and by the spatial period P of the periodic amplitude modulation. A numerical bifurcation analysis reveals the existence and stability properties of MAWs with arbitrary ν and P. MAWs are found to be stable for large enough ν and intermediate values of P. For different parameter values they are unstable to splitting and attractive interaction between subsequent extrema of the amplitude. Defects form from perturbed plane waves for parameter values above the SN of the corresponding MAWs. The break-down of phase chaos with average phase gradient ν≠0 (“wound-up phase chaos”) is thus related to these SNs. A lower bound for the break-down of wound-up phase chaos is given by the necessary presence of SNs and an upper bound by the absence of the splitting instability of MAWs.

A model for cyst lumen expansion and size regulation via fluid secretion.

Many internal epithelial organs derive from cysts, which are tissues comprised of bent epithelial cell layers enclosing a lumen. Ion accumulation in the lumen drives water influx and consequently water accumulation and cyst expansion. Lumen-size recognition is important for the regulation of organ size. When lumen size and cyst size are not controlled, diseases can result; for instance, renal failure of the kidney. We develop a mechanistic mathematical model of lumen expansion in order to investigate the mechanisms for saturation of cyst growth. We include fluid accumulation in the lumen, osmotic and elastic pressure, ion transport and stretch-induced cell division. We find that the lumen volume increases in two phases: first, due to fluid accumulation stretching the cells, then in the second phase, the volume increase follows the increase in cell number until proliferation ceases as stretch forces relax. The model is quantitatively fitted to published data of in vitro cyst growth and predicts steady state lumen size as a function of the model parameters.