Weibel-Palade bodies and Golgi apparatus

James Briscoe group project:

Elucidation of the transcriptional network

At the heart of neural tube patterning is a gene regulatory network (GRN). Graded Shh signalling regulates the expression of a group of transcription factors (TFs) that act as intermediaries in the interpretation of graded Shh signalling. Selective repressive and inductive interactions between pairs of transcription factors establish discrete changes in gene expression. This produces a transcriptional code that defines distinct progenitor domains and determines the subtype identity of neurons generated from each domain. The long-term goal is to identify the components and connections in this network and understand their function. Many players are known, but it is apparent that key components remain to be discovered. We have contributed to this effort by determining the function of several TFs during neural development. We now want to intensify these efforts and focus on understanding the underlying logic of the network and the structure of the functional sub-circuits that it contains.

A regulatory network of transcription factors in the neural tube

A regulatory network of transcription factors in the neural tube

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Identifying and reconstructing the neural tube GRN

We are taking a systematic approach to identify the TFs that comprise the neural tube GRN by profiling the transcriptional responses of chick neural tube cells exposed to different levels and durations of Shh signalling. We have identified chick orthologues of the set of TFs described in mammals and used this to define the TFs expressed in the neural tube controlled by Shh signalling. To assay the transcriptome we use Affymetrix microarrays, the nCounter system and high-throughput mRNA sequencing. To obtain information about the network and to test predicted linkages we assay the effect of activating and inhibiting Shh signalling in ovo and altering the expression of specific transcription factors using overexpression and RNAi. Together these analyses will be aimed at understanding the mechanism and underlying logic of gene regulation in the neural tube.

Microarray transcriptome screening

Microarray transcriptome screening

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Determining the genomic target sites of the neural tube GRN

The comprehensive understanding of the neural tube GRN requires the identification of genomic targets of the key TFs, as well as of the regulatory regions that control their expression. We have begun to define the direct interactions between specific members of the network by employing a ChIP-seq approach that identifies the sites bound by specific TFs in the GRN. These regions are analysed bioinformatically and tested using transgenic analysis in mouse and zebrafish. We are interested in identifying the genomic elements in neural progenitors that are regulated in a Shh dependent manner. These data, together with the transcriptome data will allow us to begin to reassemble the network that describes the transcriptional logic of the system.

Mapping the binding sites of transcription factors in the genome

Mapping the binding sites of transcription factors in the genome

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Selected publications

Briscoe group

Recent publications

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