Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8475894 | Mechanisms of Development | 2016 | 14 Pages |
Abstract
Pancreas organogenesis is a highly dynamic process where neighboring tissue interactions lead to dynamic changes in gene regulatory networks that orchestrate endocrine, exocrine, and ductal lineage formation. To understand the spatio-temporal regulatory logic we have used the Forkhead transcription factor Foxa2-Venus fusion (FVF) knock-in reporter mouse to separate the FVF+ pancreatic epithelium from the FVFâ surrounding tissue (mesenchyme, neurons, blood, and blood vessels) to perform a genome-wide mRNA expression profiling at embryonic days (E) 12.5-15.5. Annotating genes and molecular processes suggest that FVF marks endoderm-derived multipotent epithelial progenitors at several lineage restriction steps, when the bulk of endocrine, exocrine and ductal cells are formed during the secondary transition. In the pancreatic epithelial compartment, we identified most known endocrine and exocrine lineage determining factors and diabetes-associated genes, but also unknown genes with spatio-temporal regulated pancreatic expression. In the non-endoderm-derived compartment, we identified many well-described regulatory genes that are not yet functionally annotated in pancreas development, emphasizing that neighboring tissue interactions are still ill defined. Pancreatic expression of over 635 genes was analyzed with the mRNA in situ hybridization Genepaint public database. This validated the quality of the profiling data set and identified hundreds of genes with spatially restricted expression patterns in the pancreas. Some of these genes are also targeted by pancreatic transcription factors and show active chromatin marks in human islets of Langerhans. Thus, with the highest spatio-temporal resolution of a global gene expression profile during the secondary transition, our study enables to shed light on neighboring tissue interactions, developmental timing and diabetes gene regulation.
Keywords
ECMA1ATEGFCD49fFACSMPCChIP-SeqMAFFGFGRNsNPYGHRPax6IPSCGCKGIPFGF23HDAC1PYYGIPRPGFHNF1AFgf10SFRP1OTX2FGF7HNF1BAGO1alpha1-antitrypsinSDF1FOXA2FGF15IHHSMARCA4HHEXHNF4ACPA1NeuroD1H3K4me3MafBGLP1JAG1Jagged1GLI3GHRLFGF8Pdx1OSR1SMARCA2FGF9H3K27acIAAPH3K4me1PTF1ASix3Retinoic acid receptor gammaFGF1Nkx6.1GRB7fibroblast growth factor 7SLC30A8NR5A2SLC2A2GLP1RPax4Ngn3Fgf20rxrgFGF6histone 3 lysine 4 trimethylationNK2 Homeobox 2orthodenticle homeobox 2ISL LIM homeobox 1SCGNfibroblast growth factor 20Ins2Ins1NK6 homeobox 1multipotent progenitorsEn1HnfIgf1isl1insulin 1insulin 2EMTPaired box 6HedgehogIndian HedgehogShhDroshaMaturity-onset diabetes of the youngRetinoic acidembryonic dayCAMHey1Induced pluripotent stem cellssonic hedgehogEDARADDMED12epidermal growth factorplacental growth factorFibroblast growth factor 1fibroblast growth factor 10fibroblast growth factor 15Fibroblast growth factor 8Fibroblast growth factor 9stromal cell-derived factor 1hepatocyte nuclear factorfibroblast growth factorfibroblast growth factor 23insulin-like growth factor 1fluorescence activated cell sortinglumLumicanExtracellular matrixMODYBMPGenome-wide association studyGWAShairy and enhancer of split 1principal componentCell adhesion moleculeNeurogenin 3Hes1Gene ontologyhistone deacetylase 1gastric inhibitory polypeptideBone morphogenetic proteinSecreted frizzled-related protein 1Islet amyloid polypeptidepeptide YYglucagon-like peptide 1Jun proto-oncogeneGATA6Epithelial–mesenchymal transitionGlucokinasegrowth hormone receptorInsulin receptor-related receptorglucagon-like peptide 1 receptorNeuropeptide Y
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Authors
Stefanie J. Willmann, Nikola S. Mueller, Silvia Engert, Michael Sterr, Ingo Burtscher, Aurelia Raducanu, Martin Irmler, Johannes Beckers, Steffen Sass, Fabian J. Theis, Heiko Lickert,