title: Spatiotemporal regulation of GLI target genes in the mammalian limb bud.
abstract: GLI proteins convert Sonic hedgehog (Shh) signaling into a transcriptional output in a tissue-specific fashion. The Shh pathway has been extensively studied in the limb bud, where it helps regulate growth through a SHH-FGF feedback loop. However, the transcriptional response is still poorly understood. We addressed this by determining the gene expression patterns of approximately 200 candidate GLI-target genes and identified three discrete SHH-responsive expression domains. GLI-target genes expressed in the three domains are predominately regulated by derepression of GLI3 but have different temporal requirements for SHH. The GLI binding regions associated with these genes harbor both distinct and common DNA motifs. Given the potential for interaction between the SHH and FGF pathways, we also measured the response of GLI-target genes to inhibition of FGF signaling and found the majority were either unaffected or upregulated. These results provide the first characterization of the spatiotemporal response of a large group of GLI-target genes and lay the foundation for a systems-level understanding of the gene regulatory networks underlying SHH-mediated limb patterning.
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, 2500 Speedway Stop A4800, Austin, TX 78712, USA.
authors.forename: Jordan P
authors.initials: JP
authors.lastname: Lewandowski
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E3638, Baltimore, MD 21205, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Du
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E3638, Baltimore, MD 21205, USA.
authors.forename: Shilu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, 2500 Speedway Stop A4800, Austin, TX 78712, USA.
authors.forename: Marian B
authors.initials: MB
authors.lastname: Powell
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, 2500 Speedway Stop A4800, Austin, TX 78712, USA.
authors.forename: Kristin N
authors.initials: KN
authors.lastname: Falkenstein
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E3638, Baltimore, MD 21205, USA.
authors.forename: Hongkai
authors.initials: H
authors.lastname: Ji
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, 2500 Speedway Stop A4800, Austin, TX 78712, USA. Electronic address: svokes@austin.utexas.edu.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Vokes
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019521:Body Patterning / Q000235:genetics / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D053823:Hedgehog Proteins / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D018878:Limb Buds / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation; D000074290:Zinc Finger Protein Gli3
chemical_list: C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C465570:Shh protein, mouse; D000074290:Zinc Finger Protein Gli3; D005346:Fibroblast Growth Factors
keywords: Cis-regulatory modules; DNA motifs; FGF; GLI; In situ hybridization; Limb development; RNAseq; Sonic hedgehog