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1.
Dev Biol ; 354(2): 267-79, 2011 Jun 15.
Article in English | MEDLINE | ID: mdl-21515253

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.


Subject(s)
Antigens, Surface/metabolism , Fibroblast Growth Factor 10/metabolism , Fibroblast Growth Factor 9/metabolism , Gene Expression Regulation, Developmental , Lung/growth & development , Mesoderm/metabolism , Morphogenesis , RNA-Binding Proteins/metabolism , Animals , ELAV Proteins , ELAV-Like Protein 1 , Lung/metabolism , Mice , Mice, Transgenic , T-Box Domain Proteins/metabolism
2.
Mol Cell Biol ; 29(10): 2762-76, 2009 May.
Article in English | MEDLINE | ID: mdl-19307312

ABSTRACT

HuR is an RNA-binding protein implicated in a diverse array of pathophysiological processes due to its effects on the posttranscriptional regulation of AU- and U-rich mRNAs. Here we reveal HuR's requirement in embryonic development through its genetic ablation. Obligatory HuR-null embryos exhibited a stage retardation phenotype and failed to survive beyond midgestation. By means of conditional transgenesis, we restricted HuR's mutation in either embryonic or endothelial compartments to demonstrate that embryonic lethality is consequent to defects in extraembryonic placenta. HuR's absence impaired the invagination of allantoic capillaries into the chorionic trophoblast layer and the differentiation of syncytiotrophoblast cells that control the morphogenesis and vascularization of the placental labyrinth and fetal support. HuR-null embryos rescued from these placental defects proceeded to subsequent developmental stages but displayed defects in skeletal ossification, fusions in limb elements, and asplenia. By coupling gene expression measurements, data meta-analysis, and HuR-RNA association assays, we identified transcription and growth factor mRNAs controlled by HuR, primarily at the posttranscriptional level, to guide morphogenesis, specification, and patterning. Collectively, our data demonstrate the dominant role of HuR in organizing gene expression programs guiding placental labyrinth morphogenesis, skeletal specification patterns, and splenic ontogeny.


Subject(s)
Antigens, Surface/metabolism , Morphogenesis , Placenta , RNA-Binding Proteins/metabolism , Animals , Antigens, Surface/genetics , Cells, Cultured , ELAV Proteins , ELAV-Like Protein 1 , Female , Gene Expression Regulation, Developmental , Mice , Mice, Inbred C57BL , Mice, Transgenic , Musculoskeletal Abnormalities/genetics , Musculoskeletal Abnormalities/pathology , Phenotype , Placenta/anatomy & histology , Placenta/embryology , Pregnancy , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA-Binding Proteins/genetics , Spleen/abnormalities , Spleen/embryology
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