Biomedical subjects

Dagmar Iber

Publications and source records attributed to Dagmar Iber.

7 recordsLinked to original sources

PubMed2006

The mechanism of sudden stripe formation during dorso-ventral patterning in Drosophila.

The front and back (ventral and dorsal part respectively) of arthropods and chordates are defined by a highly conserved mechanism during early embryonic development [De Robertis and Kuroda in Annu. Rev. Cell Dev. Biol. 20, 285-308 (2004)]. An important feature is the sudden formation of a narrow midline peak of signaling. Mathematical models have helped to improve our understanding of the underlying mechanism [Eldar et al. in Nature 419(6904), 304-308 (2002); Mizutani in Dev. Cell 8(6), 915-924 (2005); Shimmi et al. in Cell 120(6), 873-886, (2005)]. In particular, the most recent model shows that diffusion and receptor-dependent degradation of the morphogen together with protease-mediated cleavage of a carrier protein for the morphogen are sufficient for the sudden generation of a sharp midline peak [Mizutani in Dev. Cell 8(6), 915-924 (2005)]. How these processes give rise to the observed pattern and how sensitive the model is to changes in parameter values has, however, not been resolved by this numerical study. By analysing the model in detail, we find that the sudden formation of a signaling peak is the consequence of the inversion of the gradient of the morphogen-carrier complex in the dorsal domain. As a consequence ligand is suddenly transported into rather than out of the midline, and a midline peak forms. We further show that a two-component carrier complex, consisting of Sog and Tsg, is required for abrupt peak formation. We derive quantitative conditions for the time and concentration at which the peak forms. We identify the receptor concentration, the ligand production and degradation rates, and the carrier production, diffusion, and cleavage rates as parameters to which the model is sensitive. Numerical studies confirm our analysis.

Animals↗

PubMed2006

A quantitative study of the benefits of co-regulation using the spoIIA operon as an example.

The distribution of most genes is not random, and functionally linked genes are often found in clusters. Several theories have been put forward to explain the emergence and persistence of operons in bacteria. Careful analysis of genomic data favours the co-regulation model, where gene organization into operons is driven by the benefits of coordinated gene expression and regulation. Direct evidence that coexpression increases the individual's fitness enough to ensure operon formation and maintenance is, however, still lacking. Here, a previously described quantitative model of the network that controls the transcription factor sigma(F) during sporulation in Bacillus subtilis is employed to quantify the benefits arising from both organization of the sporulation genes into the spoIIA operon and from translational coupling. The analysis shows that operon organization, together with translational coupling, is important because of the inherent stochastic nature of gene expression, which skews the ratios between protein concentrations in the absence of co-regulation. The predicted impact of different forms of gene regulation on fitness and survival agrees quantitatively with published sporulation efficiencies.

Bacillus subtilis↗

PubMed2006

A computational analysis of the impact of the transient genetic imbalance on compartmentalized gene expression during sporulation in Bacillus subtilis.

Sporulation in Bacillus subtilis serves as paradigm for the development of two different cell types (mother cell and prespore) from a single cell. Differential gene expression is achieved by restricting the activation of the key transcription factor sigmaF to the smaller prespore. By use of a combination of mathematical and experimental techniques we have recently shown that the volume difference determines cell fate and that the accumulation of the phosphatase SpoIIE on the asymmetrically placed septum is sufficient for prespore-specific sigmaF activation. Since compartmentalized gene expression is still obtained when SpoIIE cannot accumulate on the septum a number of alternative mechanisms have been proposed. These mechanisms focus on the difference in gene content between mother cell and prespore immediately after septation. Here the computational model is employed to show that under physiological conditions the transient genetic imbalance is unlikely to affect the septation-dependent release of sigmaF. The duration of the transient genetic imbalance is too short for the degradation of SpoIIAB to have an impact on the release of sigmaF. Moreover, the existence of an elusive IIE inhibitor, which has been proposed to become depleted in the prespore because of the transient genetic imbalance, is shown to be inconsistent with available experimental data. We conclude that the volume difference between the two compartments is the main determinant of cell fate.

Bacillus subtilis↗

PubMed2006

The mechanism of cell differentiation in Bacillus subtilis.

Sporulation in Bacillus subtilis serves as a model for the development of two different cell types from a single cell. Although much information has been accumulated about the mechanisms that initiate the developmental programmes, important questions remain that can be answered only by quantitative analysis. Here we develop, with the help of existing and new experimental results, a mathematical model that reproduces published in vitro experiments and explains how the activation of the key transcription factor is regulated. The model identifies the difference in volume between the two cell types as the primary trigger for determining cell fate. It shows that this effect depends on the allosteric behaviour of a key protein kinase and on a low rate of dephosphorylation by the corresponding phosphatase; both predicted effects are confirmed experimentally.

Allosteric Regulation↗

PubMed2006

An analysis of B cell selection mechanisms in germinal centers.

Affinity maturation of antibodies during immune responses is achieved by multiple rounds of somatic hypermutation and subsequent preferential selection of those B cells that express B cell receptors with improved binding characteristics for the antigen. The mechanism underlying B cell selection has not yet been defined. By employing an agent-based model, we show that for physiologically reasonable parameter values affinity maturation can be driven by competition for neither binding sites nor antigen--even in the presence of competing secreted antibodies. Within the tested mechanisms, only clonal competition for T cell help or a refractory time for the interaction of centrocytes with follicular dendritic cells is found to enable affinity maturation while generating the experimentally observed germinal centre characteristics and tolerating large variations in the initial antigen density.

Animals↗

PubMed2006

Integrin activation--the importance of a positive feedback.

Integrins mediate cell adhesion and are essential receptors for the development and functioning of multicellular organisms. Integrin activation is known to require both ligand and talin binding and to correlate with cluster formation but the activation mechanism and precise roles of these processes are not yet resolved. Here mathematical modeling, with known experimental parameters, is used to show that the binding of a stabilizing factor, such as talin, is alone insufficient to enable ligand-dependent integrin activation for all observed conditions; an additional positive feedback is required.

Feedback↗

PubMed2002

A mathematical model for germinal centre kinetics and affinity maturation.

We present a mathematical model which reproduces experimental data on the germinal centre (GC) kinetics of the primed primary immune response and on affinity maturation observed during the reaction. We show that antigen masking by antibodies which are produced by emerging plasma cells can drive affinity maturation and provide a feedback mechanism by which the reaction is stable against variations in the initial antigen amount over several orders of magnitude. This provides a possible answer to the long-standing question of the role of antigen reduction in driving affinity maturation. By comparing model predictions with experimental results, we propose that the selection probability of centrocytes and the recycling probability of selected centrocytes are not constant but vary during the GC reaction with respect to time. It is shown that the efficiency of affinity maturation is highest if clones with an affinity for the antigen well above the average affinity in the GC leave the GC for either the memory or plasma cell pool. It is further shown that termination of somatic hypermutation several days before the end of the germinal centre reaction is beneficial for affinity maturation. The impact on affinity maturation of simultaneous initiation of memory cell formation and somatic hypermutation vs. delayed initiation of memory cell formation is discussed.

Antibody Affinity↗