title: Reconstruction of the gene regulatory network involved in the sonic hedgehog pathway with a potential role in early development of the mouse brain.
abstract: The Sonic hedgehog (Shh) signaling pathway is crucial for pattern formation in early central nervous system development. By systematically analyzing high-throughput in situ hybridization data of E11.5 mouse brain, we found that Shh and its receptor Ptch1 define two adjacent mutually exclusive gene expression domains: Shh+Ptch1- and Shh-Ptch1+. These two domains are associated respectively with Foxa2 and Gata3, two transcription factors that play key roles in specifying them. Gata3 ChIP-seq experiments and RNA-seq assays on Gata3-knockdown cells revealed that Gata3 up-regulates the genes that are enriched in the Shh-Ptch1+ domain. Important Gata3 targets include Slit2 and Slit3, which are involved in the process of axon guidance, as well as Slc18a1, Th and Qdpr, which are associated with neurotransmitter synthesis and release. By contrast, Foxa2 both up-regulates the genes expressed in the Shh+Ptch1- domain and down-regulates the genes characteristic of the Shh-Ptch1+ domain. From these and other data, we were able to reconstruct a gene regulatory network governing both domains. Our work provides the first genome-wide characterization of the gene regulatory network involved in the Shh pathway that underlies pattern formation in the early mouse brain.
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Liu
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xuelong
authors.initials: X
authors.lastname: Wang
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Haifang
authors.initials: H
authors.lastname: Wang
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000254:growth & development* / Q000378:metabolism; D001923:Brain Chemistry / Q000235:genetics*; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D053263:Gene Regulatory Networks / Q000235:genetics*; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D009928:Organ Specificity; D016716:PC12 Cells; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; C000606239:Ptch1 protein, rat; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse