title: Spry2 regulates signalling dynamics and terminal bud branching behaviour during lung development.
abstract: Development of mammalian lung involves reiterative outgrowth and branching of an epithelial tube into the surrounding mesenchymal bed. Each coordinated growth and branching cycle is driven by reciprocal signalling between epithelial and adjacent mesenchymal cells. This signalling network includes FGF, SHH, BMP4 and other pathways. We have characterized lung defects in 36Pub mice carrying a deletion that removes an antagonist of FGF signalling, Spry2. Spry2 deficient mice show an enlarged cystic structure located in the terminus of each lobes. Our study shows that Spry2 deficient lungs have reduced lung branching and the cystic structure forms in the early lung development stage. Furthermore, mice carrying a targeted disruption of Spry2 fail to complement the lung phenotype characterized in 36Pub mice. A Spry2-BAC transgene rescues the defect. Interestingly, cystic structure growth is accompanied by the reduced and spatially disorganized expression of Fgf10 and elevated expression of Shh and Bmp4. Altered signalling balance due to the loss of Spry2 causes a delayed branch cycle and cystic growth. Our data underscores the importance of restricting cellular responsiveness to signalling and highlights the interplay between morphogenesis events and spatial localization of gene expression.
authors.affiliation: Shenzhen University Diabetes Center, AstraZeneca-Shenzhen University Joint Institute of Nephrology,Department of Physiology,Shenzhen University Health Science Center,Shenzhen 518060,China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Biomedical Sciences,Cornell University,Ithaca,NY 14853,USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D051526:Fibroblast Growth Factor 10 / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008168:Lung / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C465570:Shh protein, mouse; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse
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