title: HuR controls lung branching morphogenesis and mesenchymal FGF networks.
abstract: Lung development is controlled by regulatory networks governing mesenchymal-epithelial interactions. Transcription factors and signaling molecules are known to participate in this process, yet little is known about the post-transcriptional regulation of these networks. Here we demonstrate that the RNA-binding protein (RBP) HuR is an essential regulator of mesenchymal responses during lung branching. Its epiblast-induced deletion blocked the morphogenesis of distal bronchial branches at the initiation of the pseudoglandular stage. The phenotype originated from defective mesenchymal responses since the conditional restriction of HuR deletion in epithelial progenitors did not affect distal branching or the completion of lung maturation. The loss of HuR resulted in the reduction of the key inducer of bud outgrowth and endodermal branching, FGF10 and one of its putative transcriptional regulators, Tbx4. Furthermore, exogenous FGF10 could rescue the branching defect of affected lung buds. HuR was found to bind and control the Fgf10 and Tbx4 mRNAs; as a result its deletion abolished their inducible post-transcriptional regulation by the mesenchymal regulator FGF9. Our data reveals HuR as the first RBP identified to play a dominant role in lung development and as a key post-transcriptional regulator of networks guiding tissue remodeling during branching morphogenesis.
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", 16672 Vari, Greece.
authors.forename: Nikos
authors.initials: N
authors.lastname: Sgantzis
authors.forename: Anthie
authors.initials: A
authors.lastname: Yiakouvaki
authors.forename: Eumorphia
authors.initials: E
authors.lastname: Remboutsika
authors.forename: Dimitris L
authors.initials: DL
authors.lastname: Kontoyiannis
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism*; D051525:Fibroblast Growth Factor 9 / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D008168:Lung / Q000254:growth & development* / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D016601:RNA-Binding Proteins / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C496464:Fgf10 protein, mouse; C496460:Fgf9 protein, mouse; D051526:Fibroblast Growth Factor 10; D051525:Fibroblast Growth Factor 9; D016601:RNA-Binding Proteins; D020825:T-Box Domain Proteins; C103177:Tbx4 protein, mouse