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Pilz, Gregor-Alexander (2014): Characterization of progenitor cells during the development of the ventral telencephalon of the mouse. Dissertation, LMU München: Medizinische Fakultät



During development of the mammalian telencephalon stem cells and more lineage restricted progenitor cells give rise to all cell types which later are contributing to this fascinatingly orchestrated organ. Initially, at the stage of neuroepithelial cells, these stem cells increase their pool by symmetric proliferative divisions and later, when matured to radial glia (RG) cells they give rise to neurons either directly, or indirectly via intermediate progenitors. At later stages of development, radial glia generate glial progenitor cells or differentiate to glial cells directly. How stem cells orchestrate this sequel of tissue genesis has been unraveled by pioneer studies focusing on stem cells of the murine cerebral neocortex. However, the ways how one of the biggest brain regions of the murine brain, the ventral telencephalon which later forms the basal ganglia, facilitates this process, have been largely unknown. Over the past years, increasing interest has been put forward in understanding how the human cortex and its dramatically expanded surface with gyri and sulci is build up on a cellular level during embryonic development. Studies both on embryonic human and primate brains revealed that an expanded germinal zone, the outer subventricular zone (OSVZ), seeded with a heterogeneous population of progenitor cells which are rare in lissencepahlic brains, is responsible to form this enormously elevated brain region. However, both human and primate material is rare and genetically modified models are not available. To investigate the cellular mechanisms taking place in an expanded mammalian brain region in the mouse would be of great interest technically and from an evolutionary perspective. Therefore, live-imaging studies of individual progenitor cells in embryonic brainslices which have been labeled in the lateral ganglionic eminence (LGE) by in-utero electroporation were carried out to reveal lineages emanating from single RG cells. The development of the ventral telencephalon precedes that of the dorsal telencephalon, the cerebral neocortex, and already at early stages prominent bulges begin t form into the ventricular lumen. One characteristic of ventral forebrain development is the early appearance of a non-apically dividing cell population away from the ventricle, which outnumbers from stages of midneurogenesis on apically dividing cells. Amongst these non-apically dividing cells a proportion divides in the ventricular zone, a region that in the neocortex is largely devoid of mitotic cells. These subapically dividing cells were termed according to their location subapical progenitors (SAP). The characterization of these SAPs both by immunohistochemistry and live imaging revealed a morphologically heterogeneous population, with cells bearing processes towards apical, basal or both directions in addition to cells without processes resembling the morphology of basal progenitors, during mitosis. Indeed, bipolar cells amongst these SAPs were characterized as a new type of radial glia, which does not reach the ventricular surface for mitosis but divides in the VZ and generates a basally migrating bRG. By this SAPs contribute to the seeding of the LGE SVZ with a cell type that is characteristic for enlarged SVZ, like the OSVZ in gyrified brains and fundamental for the formation of gyri and sulci. The longterm observation of RG lineages in the LGE uncovered the potential to generate large progeny at midneurogenesis. RG give rise to daughter cells which divide once more in the ventricular zone and generate cells with further proliferative potential, thereby amplifying the cellular output. This amplification of progenitor cells goes along with a shortening in cell cycle length, a feature observed also in the expanded germinal zones of gyrified cortices. In conclusion the developing murine LGE turns out to be a suitable model to study the cellular mechanisms of an expanded brain region.