This proposal is based on two novel findings that identify both Sox9 and Hox5 as critical players in lung development. In addition to identifying novel roles for these transcription factors in early lung patterning and branching morphogenesis, our preliminary evidence suggests that Hox5 regulates Wnt signaling in the mesenchyme to control mesenchyme-epithelial crosstalk upstream of Sox9 expression in both the mesenchyme and epithelium. By identifying novel molecular mechanisms by which Hox5 and Sox9 regulate lung development, the proposed work will add significant new data to our existing understanding of lung organogenesis. Furthermore, the proposed experiments are designed to synthesize a comprehensive view of how Sox9 and Hox5 integrate with the Wnt/?-catenin signaling pathway to regulate early events in lung development, including patterning, branching morphogenesis, proliferation and differentiation. In order to fully elucidate this novel Hox-Wnt-Sox signaling axi, we will define Hox5- and Sox9-mediated molecular regulation of lung development and determine the mechanisms by which Hox5 modulates Wnt/?-catenin signaling to control mesenchymal-epithelial crosstalk and Sox9 expression.
Mutations in human SOX9 can lead to several inherited genetic birth defects, including severe defects of the respiratory system. Babies born with mutations in SOX9 often die in the neonatal period from respiratory distress. Our proposal will define a novel mesenchymal to epithelial signaling axis that controls multiple aspects of lung development, including proper spatiotemporal expression of Sox9. These studies will provide novel mechanistic insights into lung development and congenital disease.
|Aurora, Megan; Spence, Jason R (2016) hPSC-derived lung and intestinal organoids as models of human fetal tissue. Dev Biol 420:230-238|
|Dye, Briana R; Miller, Alyssa J; Spence, Jason R (2016) How to Grow a Lung: Applying Principles of Developmental Biology to Generate Lung Lineages from Human Pluripotent Stem Cells. Curr Pathobiol Rep 4:47-57|
|Dye, Briana R; Dedhia, Priya H; Miller, Alyssa J et al. (2016) A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids. Elife 5:|
|Larsen, Brian M; Hrycaj, Steven M; Newman, Micaleah et al. (2015) Mesenchymal Hox6 function is required for mouse pancreatic endocrine cell differentiation. Development 142:3859-68|
|Hrycaj, Steven M; Dye, Briana R; Baker, Nicholas C et al. (2015) Hox5 Genes Regulate the Wnt2/2b-Bmp4-Signaling Axis during Lung Development. Cell Rep 12:903-12|
|Dye, Briana R; Hill, David R; Ferguson, Michael A H et al. (2015) In vitro generation of human pluripotent stem cell derived lung organoids. Elife 4:|
|Rockich, Briana E; Hrycaj, Steven M; Shih, Hung Ping et al. (2013) Sox9 plays multiple roles in the lung epithelium during branching morphogenesis. Proc Natl Acad Sci U S A 110:E4456-64|
|Di Meglio, Thomas; Kratochwil, Claudius F; Vilain, Nathalie et al. (2013) Ezh2 orchestrates topographic migration and connectivity of mouse precerebellar neurons. Science 339:204-7|