Weibel-Palade bodies and Golgi apparatus

François Guillemot group project:

Regulating gene expression in neural progenitors

The developing nervous system contains vast arrays of neurons of different types organized in highly reproducible patterns that prefigure the formation of neuronal circuits. Achieving this level of organization requires that genes involved in neurogenic programmes are activated in appropriate brain regions and at a correct time.

Understanding how gene expression is regulated in the developing brain is an important aim in Developmental Neuroscience. We have shown that proneural bHLH transcription factors control the specification of neuronal identities throughout the nervous system. However, the same proneural proteins promote the generation of different types of neurons in different regions of the nervous system (e.g. Neurogenin2 specifies glutamatergic projection neurons in the cerebral cortex, dopaminergic neurons in the midbrain and cholinergic motor neurons in the spinal cord; see Bertrand et al., 2002; Parras et al., 2002). Proneural protein activity, like that of many transcription factors regulating developmental processes, is therefore cell context-dependent (see Guillemot, 2007). Moreover, genome-wide characterization of the transcriptional programmes activated during neurogenesis (Gholke et al., 2008 and unpublished data) shows that proneural proteins activate different targets during different phases of neurogenesis. Our goal is to determine the contribution of transcriptional mechanisms and epigenetic mechanisms such as chromatin organization in the spatial and temporal control of neurogenic programmes, and in controlling the competence of different types of progenitors and differentiated cells to undergo neurogenesis (reprogramming).

To address these issues, we study how proneural proteins regulate the expression of their transcriptional targets in a spatially, temporally and cell type-specific manners. We use chromatin immunoprecipitation coupled to promoter arrays (ChIP-chip) and high throughput sequencing (ChIP-seq) and expression profiling to characterize the transcriptional programmes regulated by proneural factors and to examine promoter occupancy and chromatin remodelling (unpublished work). We also use bioinformatics, proteomics, biochemical approaches and transgenic reporter assays to characterize regulatory elements bound by proneural factors and identify co-regulators (Castro et al., 2006 and unpublished data).

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The proneural protein Ngn2 drives LacZ reporter gene expression in the embryonic cerebral cortex by binding to an evolutionary conserved regulatory element.

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