| The majority of the neurons in the mammalian cerebral cortex are glutamatergic excitatory neurons that have a specific migration pattern and a well-defined `pyramidal' morphology. Pyramidal neurons migrate on a radial glia scaffold to reach a layer-specific destination in the cortex and extend two polarized processes: the apical dendrite and the axon. Defining molecular mechanisms of migration and morphogenesis are key to understanding circuit formation in the developing cortex.;Recent studies have demonstrated that GSK-3 has a critical role in controlling neuronal number through regulation of radial progenitor proliferation and intermediate precursor amplification. However, only in vitro work has addressed GSK-3 functions related to cortical neuronal morphogenesis. The primary conclusion has been that, downstream of RTK/PI3K pathways, GSK-3 inhibition favors axon specification over dendrite formation. Often, in vitro studies cannot be recapitulated in vivo. For my thesis, I have generated mouse lines that allow for the in vivo deletion of GSK-3 in newly born excitatory neurons of the cerebral cortex.;I have identified a cell autonomous requirement for GSK-3 signaling in neuronal migration. GSK-3 regulation is specific for radial migration as tangential migration is not affected. Additionally, GSK-3 signaling regulates key aspects of morphogenesis including development of the apical dendrite and orientation of the basal arbor. Interestingly, GSK-3 regulation of migration is not mediated by beta-catenin signaling and appears to be independent of the RTK/PI3K pathways. Rather, I find strong reductions in phosphorylation of two microtubule associated proteins: the migration mediator Doublecortin and the semaphorin signaling mediator CRMP-2. Further, the abnormalities in dendritic morphology I describe bear similarities to abnormal semaphorin signaling.;I conclude that GSK-3 signaling is essential for proper circuit formation and connectivity in the developing cerebral cortex via regulation of neuronal migration and polarized morphological elaboration. I further demonstrate that GSK-3 regulation of developing cortical neurons is through a signaling cascade that is distinct from regulation of progenitor homeostasis. My work emphasizes the importance of GSK-3 signaling in multiple aspects of the development of the mammalian cerebral cortex. |
