title: A computational model of the effect of gene misexpression on the development of cortical areas.
abstract: Brain function depends on the specialisation of brain areas. In the murine cerebral cortex, the development of these areas depends on the coordinated expression of several genes in precise spatial patterns in the telencephalon during embryogenesis. Manipulating the expression of these genes during development alters the positions and sizes of cortical areas in the adult. Qualitative data also show that these genes regulate each other's expression during development so that they form a regulatory network with many feedback loops. However, it is currently unknown which regulatory interactions are critical to generating the correct expression patterns to lead to normal cortical development. Here, we formalise the relationships inferred from genetic manipulations into computational models. We simulate many different networks potentially consistent with the experimental data and show that a surprising diversity of networks produce similar results. This demonstrates that existing data cannot uniquely specify the network. We conclude by suggesting experiments necessary to constrain the model and help identify and understand the true structure of this regulatory network.
authors.affiliation: Queensland Brain Institute, The University of Queensland, St Lucia, QLD, 4072, Australia, clareg@gmail.com.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Giacomantonio
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Goodhill
mesh_terms: D000465:Algorithms; D000818:Animals; D019521:Body Patterning / Q000235:genetics; D051838:COUP Transcription Factor I / Q000172:deficiency / Q000235:genetics; D002540:Cerebral Cortex / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism*; D003198:Computer Simulation; D003491:Cybernetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000172:deficiency / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D008959:Models, Neurological; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D051838:COUP Transcription Factor I; D004268:DNA-Binding Proteins; D051524:Fibroblast Growth Factor 8; D018398:Homeodomain Proteins; D064231:Nestin; D012333:RNA, Messenger; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins; C496457:Fgf8 protein, mouse; C577485:Nes protein, mouse; C490035:Sp8 protein, mouse