T cells missing Rac GTPases

François Guillemot group project:

Elucidating the genetic programmes for neurogenesis and gliogenesis

The differentiation of neural stem cells into specific types of neurons and glia cells is a complex process which involves a succession of cellular steps, including the commitment of the daughters of stem cells to a neuronal or glia cell fate, the specification of regional identities, the expansion of progenitor populations followed by the arrest of their divisions, the migration of newborn cells from the progenitor zones to their final location and the initiation of terminal differentiation.

Some years ago, we and others have shown that proneural bHLH transcription factors play a major role in the regulation of neurogenesis in vertebrate embryos (see Bertrand et al., 2002). Expression of a proneural gene is both necessary and sufficient to activate a full programme of neurogenesis in stem cells. Extensive genetic analysis has shown that proneural factors coordinate the different steps of neurogenesis into a coherent developmental programme. In addition, the proneural protein Mash1 is also required for the generation of oligodendrocytes (see Parras et al., 2007).

In contrast, much less is known of the molecular mechanisms underlying each of the cellular steps that stem cells go through to generate differentiated progenies. Our aim is to better understand how the fate specification, proliferation, migration and terminal differentiation of precursor cells are controlled at a molecular level, focusing on the embryonic telencephalon (cerebral cortex and basal ganglia) and the adult dentate gyrus and subependymal zone.

To achieve this, we characterize the role in neurogenesis and gliogenesis of various candidate genes, including genes activated downstream of proneural factors (see Research project Regulating gene expression in neural progenitors), using a large range of functional assays such as the analysis of transgenic and knockout mice as well as gene overexpression and gene knockdown by electroporation in utero, in brain explants and in stem cell cultures. We have shown for example that proneural factors induce the expression of small GTP-binding proteins that have essential roles in the migration of neurons of the developing cerebral cortex and other regions of the embryonic and adult brain (see Heng et al., 2008 and unpublished data)

Neurons

Neurons

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Neurons electroporated with a plasmid expressing the reporter protein GFP migrate in the cerebral cortex of a mouse embryo

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