James Briscoe: Projects

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 currently focus on understanding the underlying logic of the network and the structure of the functional sub-circuits that it contains.

A Transcriptional Network Interprets Graded Shh Signalin

A Transcriptional Network Interprets Graded Shh Signalin

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 neural progenitors exposed to different levels and durations of Shh signalling. To obtain information about the network and to test predicted linkages we assay the effect of activating and inhibiting Shh signalling and perturbing the expression of specific transcription factors. Together these analyses are aimed at understanding the mechanism and underlying logic of gene regulation and to test these we construct and test mathematical models of the transcriptional network.

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 investigated bioinformatically and tested using transgenic analysis. 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

Selected publications

Cohen, M; Page, KM; Perez-Carrasco, R; Barnes, CP and Briscoe, J (2014) A theoretical framework for the regulation of Shh morphogen-controlled gene expression. Development 141, 3868-3878

Moore S, Ribes V, Terriente J, Wilkinson D, Relaix F, Briscoe J. (2013) Distinct regulatory mechanisms act to establish and maintain Pax3 expression in the developing neural tube. PLoS Genet 9:e1003811

Sasai N, Kutejova E, Briscoe J. (2014) Integration of signals along orthogonal axes of the vertebrate neural tube controls progenitor competence and increases cell diversity. PLoS Biol.12:e1001907.

James Briscoe

James Briscoe

james.briscoe@crick.ac.uk
+44 (0)20 379 61388

  • Qualifications and history
  • 1996 PhD Imperial Cancer Research Fund/Kings College, London, UK
  • 1996 Post doctoral fellow Columbia University, New York, USA
  • 2000 Group Leader, Medical Research Council National Institute for Medical Research, London, UK
  • 2015 Group Leader, the Francis Crick Institute, London, UK