The cerebral cortex is one of the most complex and important structures in our brain. In correlation with its elaborate functions, the neocortex comprises a huge diversity of neuronal types, each cortical neuron displaying specific patterns of differentiation and connectivity. During development, embryonic progenitors sequentially generate the diverse repertoire of neuronal subtypes that will form the cortex (from early-born Cajal-Retzius neurons to later-generated pyramidal neurons). The molecular mechanisms accounting for this striking capacity of cortical progenitors to generate all types of neurons are unknown. The aim of my project is to identify the mechanisms of cortical neurogenesis that further have crucial implications for our understanding of pathological brain development and for the rational design of replacement therapies of neurodegenerative diseases. In this matter, the host lab (Dr Pierre Vanderhaeghen lab) has developed a particularly adequate model. In this system, murine embryonic stem (ES) cells efficiently generate neurons that share all landmarks of genuine neurons of the cerebral cortex. Strikingly, developing neurons recapitulate the major milestones of in vivo development, including the sequential generation of distinct subtypes of neurons. In this unique model of temporal neurogenesis, I will test candidate genes such as the transcription factors FoxG1, Sp8 (both affecting mammalian brain development through unknown mechanisms), and Chinmo homologues zBTB20-24 (Chinmo affecting temporal neurogenesis in drosophila), using an inducible system of gene expression. By microarrays experiments I will determine the gene expression profiling of generated neurons. This will allow to look for gene signatures of cortical neurons generated from ES cells, and to identify other genes associated with cortical neurogenesis. Attractive candidates will be tested in vitro and then in vivo in the mouse for their physiological relevance.
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