No description available.

No description available.

No description available.

No description available.

During development, Dictyostelium discoideum cells assume muticellularity via their collective aggregation. Cell-cell adhesion is required for morphogenesis, cell differentiation, cell sorting and gene expression during development. TgrC1 is a heterophilic cell adhesion molecule which is indispendable for complete development. TgrC1 can be considered as the most important cell adhesion molecule for D. discoideum development because deletion of the tgrC1 gene completely arrests development at the loose aggregate stage and inhibits fruiting body formation. In order to investigate the biological role of TgrC1 during development, I have chosen to identify and charactize the extracellular heterophilic partner and the cytoplasmic binding partner(s) of TgrC1. Using different biochemical approaches, we identified TgrB1 as the heterophilic binding partner of TgrC1 and demonstrated that their association is mediated through IPT/TIG domains in the extracellular region of both proteins. Both tgrB1 and tgrC1 share the same transcriptional promoter and their spatiotemporal expression pattern is identical during development. We also examined the assembly of TgrC1-TgrB1 complexes via the split green fluorescence protein complementation assay and the fluorescence resonance energy transfer approach. Whereas TgrC1 is capable of forming cis-homodimers spontaneously, cis-homodimerization of TgrB1 depends on its trans-interaction with TgrC1. A model of the assembly process has been proposed. To investigate signalling events initiated by the interaction between TgrB1 and TgrC1, pull-down assays were employed and led to the identification of myosin heavy chain kinase C as the cytoplamic partner of TgrC1. Mutational analysis showed that the basic residues in the short cytoplasmic domain of TgrC1 are critical to the binding with MHCK-C. Disruption of the interation between MHCK-C and TgrC1 results in an alteration of cell motility at the aggregation stage and aberrant cell sorting in slugs. These studies have highlighted the role of TgrB1-TgrC1 complexes in the regulation of morphogenesis during Dictyostelium development.

The evolution and development of multicellular organisms requires cells to differentiate, interact and "collaborate". Our understanding of the molecular mechanisms is still hazy. In this dissertation mathematical modelling is used to integrate available experimental data and to make testable predictions about such mechanisms. The thesis is split into three parts, each of which addresses one of the three challenges: differentiation, adhesion and collaboration. In the first part, a mathematical model is developed to explain how, in the absence of polarizing cues from the environment, sister cells with identical genomes can follow distinct routes of differentiation. It is shown that difference in cell size, resulting from asymmetric cell division, is sufficient to induce differential cell fate in Bacillus subtilis. The model predicts that this effect depends on the allosteric behaviour of a kinase and the low catalytic rate of the corresponding phosphatase; both properties were subsequently confirmed in experiments. During the development of multicellular organisms, differentiation can arise in response to gradients. By example of dorso-ventral patterning it is shown how a shallow maternal gradient can be converted into a sharp pattern. In the second part, a model for cell adhesion via integrins is developed, and it is shown that, for physiological parameters, binding of a ligand and of a stabilizing factor such as talin are insufficient for ligand-dependent integrin activation, and that a positive signaling feedback is required. In the final part, antibody affinity maturation is studied as an example for division of labour between collaborating cells. A novel B cell selection mechanism, based on competition for T cell help rather than for antigen, is proposed and shown to reconcile heretofore inexplicable experimental observations. Such a mechanism requires B cells to discriminate among different affinities of binding, and it is further shown that this can be achieved if B cell signaling is initiated by antigen-dependent receptor-inhibitor segregation. The predictions of the model match experimental measurements quantitatively.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Nevada, Reno, 2008. / "May, 2008." Includes bibliographical references. Online version available on the World Wide Web.

Thesis (Ph.D.)--Ohio University, November, 2007. / Abstract only has been uploaded to OhioLINK. Includes bibliographical references (leaves 152-164)

Thesis (Ph.D.)--University of Delaware, 2007. / Principal faculty advisor: Ulhas Naik, Dept. of Biological Sciences. Includes bibliographical references.