HuR controls lung branching morphogenesis and mesenchymal FGF networks

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.

Research highlights
► The loss of the RNA-binding protein HuR blocks lung branching morphogenesis in the mouse.
► HuR controls mesenchymal but not epithelial responses during branching.
► HuR's loss affected Tbx4 & FGF10 production but not mesenchymal proliferation.
► Exogenous FGF10 rescues the branching phenotype.
► HuR targets the Tbx4 and Fgf10 mRNAs and regulates their use by FGF9-insitigated signals.