Biomedical subjects

Steven D Webb

Publications and source records attributed to Steven D Webb.

3 recordsLinked to original sources

PubMed2004

Intra-membrane ligand diffusion and cell shape modulate juxtacrine patterning.

A key problem in developmental biology is how pattern and planar polarity are transmitted in epithelial structures. Examples include Drosophila neuronal differentiation, ommatidia formation in the compound eye, and wing hair polarization. A key component for the generation of such patterns is direct cell-cell signalling by transmembrane ligands, called juxtacrine signalling. Previous models for this mode of communication have considered homogeneous distributions in the cell membrane, and the role of polarity has been largely ignored. In this paper we determine the role of inhomogeneous protein and receptor distributions in juxtacrine signalling. We explicitly include individual membrane segments, diffusive transport of proteins and receptors between these segments, and production terms with a combination of local and global responses to ligand binding. Our analysis shows that intra-membrane ligand transport is vital for the generation of long wavelength patterns. Moreover, with no ligand transport, there is no pattern formation for lateral induction, a process in which receptor activation up-regulates ligand production. Biased production of ligand also modulates patterning bifurcations and predicted wavelengths. In addition, biased ligand and receptor trafficking can lead to regular polarity across a lattice, in which each cell has the same orientation-directly analogous to patterns of hairs in the Drosophila wing. We confirm the trends in pattern wavelengths previously observed for patterns with cellular homogeneity-lateral inhibition tends to give short-range patterns, while lateral induction can give patterns with much longer wavelengths. Moreover, the original model can be recovered if intra-membrane bound receptor diffusion is included and rapid equilibriation between the sides is considered. Finally, we consider the role of irregular cell shapes and waves in such networks, including wave propagation past clones of non-signalling cells.

Animals↗

PubMed2003

Oscillations and patterns in spatially discrete models for developmental intercellular signalling.

We extend previous models for nearest neighbour ligand-receptor binding to include both lateral induction and inhibition of ligand and receptor production, and different geometries (strings of cells and hexagonal arrays, in addition to square arrays). We demonstrate the possibility of lateral inhibition giving patterns with a characteristic length scale of many cell diameters, when receptor production is included. In contrast, lateral induction combined with inhibition of receptor synthesis cannot give rise to a patterning instability under any circumstances. Interesting new dynamics include the analytical prediction and consequent numerical observation of spatiotemporal oscillations, this depends crucially on the production terms and on the relationship between the decay rates of ligand and free receptor. Our approach allows for a detailed comparison with the model for Delta-Notch interactions of Collier et al. [4], and we find that a formal reduction may be made only when the ligand receptor binding kinetics are very slow. Without such very slow receptor kinetics, spatial pattern formation via lateral inhibition in hexagonal cellular arrays requires significant activation of receptor production, a feature that is not apparent from previous analyses.

Algorithms↗

PubMedDate not supplied

Cells behaving badly: a theoretical model for the Fas/FasL system in tumour immunology.

One proposed mechanism of tumour escape from immune surveillance is tumour up-regulation of the cell surface ligand FasL, which can lead to apoptosis of Fas receptor (Fas) positive lymphocytes. Based upon this 'counterattack', we have developed a mathematical model involving tumour cell-lymphocyte interaction, cell surface expression of Fas/FasL, and their secreted soluble forms. The model predicts that (a) the production of soluble forms of Fas and FasL will lead to the down-regulation of the immune response; (b) matrix metalloproteinase (MMP) inactivation should lead to increased membrane FasL and result in a higher rate of Fas-mediated apoptosis for lymphocytes than for tumour cells. Recent studies on cancer patients lend support for these predictions. The clinical implications are two-fold. Firstly, the use of broad spectrum MMP inhibitors as anti-angiogenic agents may be compromised by their adverse effect on tumour FasL up-regulation. Also, Fas/FasL interactions may have an impact on the outcome of numerous ongoing immunotherapeutic trials since the final common pathway of all these approaches is the transduction of death signals within the tumour cell.

Apoptosis↗