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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL119215-03
Application #
8854136
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2013-08-01
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Cruz-Acuña, Ricardo; Quirós, Miguel; Huang, Sha et al. (2018) Publisher Correction: PEG-4MAL hydrogels for human organoid generation, culture, and in vivo delivery. Nat Protoc :
Miller, Alyssa J; Hill, David R; Nagy, Melinda S et al. (2018) In Vitro Induction and In Vivo Engraftment of Lung Bud Tip Progenitor Cells Derived from Human Pluripotent Stem Cells. Stem Cell Reports 10:101-119
Hrycaj, Steven M; Marty-Santos, Leilani; Cebrian, Cristina et al. (2018) Hox5 genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion. Proc Natl Acad Sci U S A 115:E10605-E10614
Miller, Alyssa J; Spence, Jason R (2017) In Vitro Models to Study Human Lung Development, Disease and Homeostasis. Physiology (Bethesda) 32:246-260
Cruz-Acuña, Ricardo; Quirós, Miguel; Farkas, Attila E et al. (2017) Synthetic hydrogels for human intestinal organoid generation and colonic wound repair. Nat Cell Biol 19:1326-1335
Ptaschinski, Catherine; Hrycaj, Steven M; Schaller, Matthew A et al. (2017) Hox5 Paralogous Genes Modulate Th2 Cell Function during Chronic Allergic Inflammation via Regulation of Gata3. J Immunol 199:501-509
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:
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; Hill, David R; Ferguson, Michael A H et al. (2015) In vitro generation of human pluripotent stem cell derived lung organoids. Elife 4:

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