Objective
The mammalian cortex, site of our cognitive functions, is a complex three dimensional environment which develops through an elaborated spatiotemporal choreography. A slight imbalance in this process can lead to devastating pathologies such as autistic spectrum disorders. While tremendous progress has been made in understanding early cortical development, several questions remain unanswered: how do minicolumns, the basic functional units of the cortex, establish their complex yet highly stereotyped organization, and what signaling pathways regulate this developmental process. In this proposal, I will use novel transgenic strategies and imaging techniques to address the following aims: 1) to characterize the ontogenesis of functional minicolumns, and 2) to investigate how activity of a key integrator of intracellular signaling pathways, Akt kinase, may influence both cortical cell commitment, migration and final positioning and the subsequent formation of functional minicolumns. To explore those questions, I will use the Brainbow technique, recently developed to drive combinatorial gene expression in a cellular population. First, this strategy will allow me to mark multiple adjacent cortical precursors with distinct labels, and thus track their progeny during minicolumn ontogenesis. Second, I will use the Brainbow approach to study Akt function by modulating its activity in a mosaic manner. To this aim, I will generate a construct able to stochastically express distinct Akt variants, showing either a constitutive action or dominant negative effect. This will allow me to investigate for the first time and in an intact developing brain how variations in the activity level of a kinase protein may differentially impact the lineage of neighboring neural precursors. This work will offer new insights on cortical development and will potentially reveal novel therapeutic targets for neuropsychiatric disorders.
Fields of science
Call for proposal
FP7-PEOPLE-2009-RG
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Funding Scheme
MC-IRG - International Re-integration Grants (IRG)Coordinator
75654 Paris
France