title: Genomic characterisation of a Fgf-regulated gradient-based neocortical protomap.
abstract: Recent findings support a model for neocortical area formation in which neocortical progenitor cells become patterned by extracellular signals to generate a protomap of progenitor cell areas that in turn generate area-specific neurons. The protomap is thought to be underpinned by spatial differences in progenitor cell identity that are reflected at the transcriptional level. We systematically investigated the nature and composition of the protomap by genomic analyses of spatial and temporal neocortical progenitor cell gene expression. We did not find gene expression evidence for progenitor cell organisation into domains or compartments, instead finding rostrocaudal gradients of gene expression across the entire neocortex. Given the role of Fgf signalling in rostrocaudal neocortical patterning, we carried out an in vivo global analysis of cortical gene expression in Fgfr1 mutant mice, identifying consistent alterations in the expression of candidate protomap elements. One such gene, Mest, was predicted by those studies to be a direct target of Fgf8 signalling and to be involved in setting up, rather than implementing, the progenitor cell protomap. In support of this, we confirmed Mest as a direct transcriptional target of Fgf8-regulated signalling in vitro. Functional studies demonstrated that this gene has a role in establishing patterned gene expression in the developing neocortex, potentially by acting as a negative regulator of the Fgf8-controlled patterning system.
authors.affiliation: Wellcome Trust/CR UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Sansom
authors.forename: Jean M
authors.initials: JM
authors.lastname: Hébert
authors.forename: Uruporn
authors.initials: U
authors.lastname: Thammongkol
authors.forename: James
authors.initials: J
authors.lastname: Smith
authors.forename: Grace
authors.initials: G
authors.lastname: Nisbet
authors.forename: M Azim
authors.initials: MA
authors.lastname: Surani
authors.forename: Susan K
authors.initials: SK
authors.lastname: McConnell
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Livesey
mesh_terms: D000818:Animals; D019521:Body Patterning; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D023281:Genomics; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D019579:Neocortex / Q000002:abnormalities / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010802:Phylogeny; D011506:Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D011506:Proteins; D014157:Transcription Factors; C103637:mesoderm specific transcript protein; D005346:Fibroblast Growth Factors