Techn. Universiẗat, Diss., 2003--Darmstadt.

Techn. University, Diss., 2003--Berlin.

Techn. Universiẗat, Diss., 2003--Darmstadt.

Universiẗat, Diss., 2005--Karlsruhe.

Zugl.: Magdeburg, Univ., Diss., 2008

Diese Dissertation analysiert zum ersten Mal STARD13, ein Protein mit einer RhoGAP-Domäne, und dessen Rolle als essentiellen Regulator der Pankreasarchitektur im Mausembryo. Es wird gezeigt, dass Stard13 anfangs im pankreatischen Endoderm exprimiert wird und später in den “Epithelspitzen” angereichert ist. Konditionelle Ablation von Stard13 im Mauspankreas beeinflusst die normale Epithelmorphogenese und die Organisation der “Epithelspitzen”. Das beeinträchtigt die Proliferation der Pankreasvorläuferzellen und führt zu Organhypoplasie. Dabei reguliert STARD13 örtlich und zeitlich Rho-Signale, die für die Morphogenese essentiell sind. Desweiteren werden die Mechanismen, die für die Entwicklung des Pankreasepithels in ein funktionierendes Organ notwendig sind, neu beleuchtet. Es wird zum Beispiel eine funktionelle Verbindung zwischen Rho-vermittelter Kontrolle der Epithelumgestaltung und der Determinierung der Organgröße hergestellt. Dabei spielt die reziproke Interaktion von actin-MAL-SRF and MAPK Signalen eine wichtige Rolle. / The development of functional organ architecture relies on coordinated morphogenesis and growth. In the developing pancreas, the branching epithelium is organized in discrete domains that delineate one specific domain of progenitor cells at the tip of the branches. Very little is known about branching morphogenesis in the pancreas and how it is coordinated with proliferation. This thesis presents the first analysis of the RhoGAP-domain-containing protein STARD13 and its role as an essential regulator of pancreas tissue architecture in the mammalian embryo. It is shown that Stard13 is expressed in the pancreatic endoderm and enriched at the distal tip of the branching epithelium. Conditional ablation of Stard13 expression in the mouse pancreas disrupts epithelial morphogenesis and tip domain organization, resulting in hampered proliferation of pancreatic progenitors and subsequent organ hypoplasia. Stard13 acts by regulating Rho signaling spatially and temporally during pancreas development. This thesis provides new insights into the mechanisms that shape pancreatic epithelium to create a mature organ and establishes a functional link between Rho-mediated control of epithelial remodeling and organ size determination, involving reciprocal interaction of actin-MAL-SRF and MAPK signaling.

Diss.--Mathematik--Berlin--Humboldt-Universität, 2000. / Notes bibliogr. Bibliogr. p. [175]-179. Index.

During animal development numerous organs with functions ranging from fluid transport to signal propagation develop into highly branched shapes and forms. To ensure organ function, the formation of their geometrical and topological as well as size-dependent properties is crucial. For example, organ geometry serves to maximize exchange area with its surroundings and organ topology controls the response to fluctuations and damage. Most importantly, organ size and proportion need to scale throughout animal growth to meet the demands of increasing body size. However, how organ geometry and topology are established and scaled in a self-organized manner, remains poorly understood. In this thesis, we present a novel theoretical framework to study the self-organized growth and scaling of branched organs. In this framework, we represent the organ outline by an infinitely thin interface and consider morphogen-controlled interface evolution in growing domains. We demonstrate that an instability in interface motion can lead to the self-organized formation of complex branched morphologies and show how the interplay between interface motion, morphogen dynamics, and domain growth controls the geometrical, topological, and size-dependent properties of the resulting structures. To understand the formation of branched structures from instabilities in morphogen-controlled interface growth, we first consider a range of different interface growth scenarios in non-growing domains. In a first approach, we present a stochastic lattice model with interface growth driven by a morphogen concentration gradient. We find a range of branched morphologies extending from self-similar fractal structures to almost circular structures with only a few branches depending on the morphogen gradient length scale. We present the Euler characteristic as an example of a topological invariant and employ it to introduce topological constraints into interface growth, leading to the formation of tree-like structures. In a second approach, we study a continuum model for morphogen-controlled interface growth. In this model, the interface has a constant tendency to grow and is inhibited by morphogen concentration. Additionally, we take into account a curvature dependency of interface growth, which leads to an effective stabilization of interface motion at small length scales. We identify branch distance and thickness as key morphological properties and discuss their regulation. We relate branch distance regulation to the interplay of destabilization from morphogen inhibition and stabilization from the curvature dependency of interface growth and explain branch thickness regulation in terms of mutual branch inhibition. By considering interface instability in different scenarios, we overall demonstrate the robustness of our approach. Finally, we apply our theoretical framework to study the branching morphogenesis of the planarian gut. The planarian gut is a highly branched organ that spans the entire organism and is responsible for the delivery of nutrients to the planarian body. Planarians undergo massive body size changes of more than one order of magnitude in organism length and thus constitute an ideal model organism to study the growth and scaling of branched organs. We reconsider our continuum model and include novel features needed to account for the organization of the planarian gut. We take into account external guiding cues that alter the orientation of branches and, most importantly, consider branching morphogenesis in a growing domain. We demonstrate that our model can account for the geometrical and topological properties of the gut and show that gut scaling can arise from to the interplay of branch growth and organism growth. Overall, we present a novel theoretical framework to study the growth and scaling of branched organs. In this framework, we demonstrate the self-organized formation of branched morphologies from instabilities in morphogen-controlled interface growth and show how the interplay of interface motion, morphogen dynamics, and system size determine geometry, topology, and size-dependent properties of the resulting structures.

Techn. Universiẗat, Diss., 2006--Darmstadt.

This dissertation deals with the potential of thermal field-flow fractionation (ThFFF) for the multidetection-based analysis of polymers with complex topology to prove its capability in resolving polymer branching characteristics from measured thermophoretic properties. For that, not yet existent but necessary profound advances in the theory of ThFFF and as well, thermophoresis of branched polymers were generated to allow a full exploitation of the method in the elucidation of polymer topology. Exemplary, two different libraries of branched polymer model systems based on aliphatic-aromatic polyesters and on a new type of short chain branched polyethylene were investigated. On top, the potential of the optimized ThFFF theory was assessed in the context of crosslinked polymer architectures and shines light onto the so far controversially debated topic of electron beam irradiation effects on thermoplastic polyurethane.