Untersuchung der Funktion des Aktin-bindenden Proteins Profilin1 in der zerebralen Kortexentwicklung der Maus

The dynamic polymerization and depolymerization of actin filaments is regulated by actin-binding proteins such as profilin1. Profilin1 not only regulates the polymerization of actin monomers on the actin filament, but also interacts with a large number of other ligands. It is involved in a variety of processes throughout the body (e. g. cell migration, proliferation and apoptosis) and has been associated with various diseases such as vascular hypertrophy and hypertension, diabetes, amyotrophic lateral sclerosis, and fragile-x-syndrome. Due to the involvement of profilin1 in many different processes such as cell migration and proliferation, it has been postulated to play an important role in healthy brain development. Previous studies on brain-specific profilin1 knock-out mice were able to show that the brain-specific deletion of profilin1 in mice leads to hypoplasia of the cerebellum, which is associated with abnormal stratification of the cerebellar cortex. Also striking were a reduced size of the neocortex, a “partial” reactive astrogliosis and folds of the cerebral cortex. The characterization of these folds and the investigation of their possible causes as well as the closer analysis of the reactive astrogliosis formed the aim of this work. The present dissertation showed that the brain-specific deletion of profilin1 leads to a transient increase in the number of bRG (basal radial glia cells) and to mislocated bIP (basal intermediate progenitor cells) in the neocortex of mice. This anomaly was triggered by a shift in the division plane of mitotic aRG (apical radial glia cells) towards more horizontal divisions. The shift in the division plane was due to a reduced anchoring of the mitotic spindle to the cell cortex, which resulted from a significant reduction in the subcortical F-actin structure of mitotic aRG. The increased number of bRG and an increased mitotic rate of the mislocated IP in turn led to a transiently increased production of neurons. In connection with the increased number of astrocytes in layer I of the cerebral cortex of the adult profilin1-deficient mice, the hypothesis arose that the folds of the cerebral cortex are due to an increased strength of individual cell layers. Furthermore, the isolated proliferation of reactive astrocytes in the adult profilin1-deficient mice could be demonstrated, which is indicative of a “complete” reactive astrogliosis. In comparison with pre-existing studies, it was found that the deletion of profilin1 could even be directly responsible for the reactivation of microglia and astrocytes. The present work clarifies the importance of profilin1 for the correct alignment of the mitotic spindle in murine aRG and provides strong indications for the importance of profilin1 for natural homeostasis in glial cells. Further investigations in this direction could provide new insights into the development and progression of neurodegenerative diseases such s polymicrogyria, lissencephaly or ALS.