title: Integration of Shh and Fgf signaling in controllingHoxgene expression in cultured limb cells.
abstract: During embryonic development, fields of progenitor cells form complex structures through dynamic interactions with external signaling molecules. How complex signaling inputs are integrated to yield appropriate gene expression responses is poorly understood. In the early limb bud, for instance, Sonic hedgehog (Shh) is expressed in the distal posterior mesenchyme, where it acts as a mediator of anterior to posterior (AP) patterning, whereas fibroblast growth factor 8 (Fgf8) is produced by the apical ectodermal ridge (AER) at the distal tip of the limb bud to direct outgrowth along the proximal to distal (PD) axis. Here we use cultured limb mesenchyme cells to assess the response of the targetHoxdgenes to these two factors. We find that they act synergistically and that both factors are required to activateHoxd13in limb mesenchymal cells. However, the analysis of the enhancer landscapes flanking theHoxDcluster reveals that the bimodal regulatory switch observed in vivo is only partially achieved under these in vitro conditions, suggesting an additional requirement for other factors.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rodrigues
authors.affiliation: Laboratory of Developmental Genomics, Federal Institute of Technology, Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Nayuta
authors.initials: N
authors.lastname: Yakushiji-Kaminatsui
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Atsuta
authors.affiliation: Laboratory of Developmental Genomics, Federal Institute of Technology, Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Andrey
authors.affiliation: Laboratory of Developmental Genomics, Federal Institute of Technology, Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schorderet
authors.affiliation: Laboratory of Developmental Genomics, Federal Institute of Technology, Lausanne, CH-1015 Lausanne, Switzerland; tabin@genetics.med.harvard.edu denis.duboule@epfl.ch.|Department of Genetics and Evolution, University of Geneva, CH-1205 Geneva, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Duboule
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115; tabin@genetics.med.harvard.edu denis.duboule@epfl.ch.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Tabin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D047369:Chromatin Immunoprecipitation; D005121:Extremities / Q000196:embryology*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D053823:Hedgehog Proteins / Q000378:metabolism*; D059014:High-Throughput Nucleotide Sequencing; D008024:Ligands; D011485:Protein Binding; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D008024:Ligands; D005346:Fibroblast Growth Factors
keywords: Hox genes; Sonic hedgehog; fibroblast growth factor; limb development