Respiratory system

We are investigating how FGF, Wnt, and BMP signaling pathways interact to regulate growth of the lung and the complex process of branching morphogenesis. We are investigating mechanisms by which micro RNAs and other epigenetic factors regulate Fgf9 expression during development and in the pathogenesis of Pleuropulmonary Blastoma, a familial pediatric lung cancer syndrome that is initiated by mutations in DICER1. We are investigating mechanisms by which FGFs are protective in lung epithelial repair and pathogenic in pulmonary fibrosis, and we are investigating mechanisms by which FGF signaling activates adult lung progenitor cells in models of adenocarcinoma and response to injury.

Lungs from control and Fgf9-/- mice

Dermo1Cre, ROSA26LacZ

ShhCre, ROSA26LacZ

Ornitz and Yin, 2012

Stages of embryonic lung development

Recent Publications:

1.    White AC, Xu J, Yin Y, Smith C, Schmid G & Ornitz DM (2006) FGF9 and SHH signaling coordinate lung growth and development through regulation of distinct mesenchymal domains. Development 133(8):1507-1517.
2.    White AC, Lavine KJ & Ornitz DM (2007) FGF9 and SHH regulate mesenchymal Vegfa expression and development of the pulmonary capillary network. Development 134(20):3743-3752.  PMCID: PMC2099314.
3.    Yin Y, White AC, Huh SH, Hilton MJ, Kanazawa H, Long F & Ornitz DM (2008) An FGF-WNT gene regulatory network controls lung mesenchyme development. Dev Biol 319(2):426-436.  PMCID: PMC2757945.
4.    Yin Y, Wang F & Ornitz DM (2011) Mesothelial- and epithelial-derived FGF9 have distinct functions in the regulation of lung development. Development 138(15):3169-3177.  PMCID: PMC3188607.
5.    Ornitz DM & Yin Y (2012) Signaling networks regulating development of the lower respiratory tract. Cold Spring Harb Perspect Biol 4(5):1-19.  PMCID: PMC3331697.
6.    Yin Y, Betsuyaku T, Garbow JR, Miao J, Govindan R & Ornitz DM (2013) Rapid induction of lung adenocarcinoma by fibroblast growth factor 9 signaling through FGF receptor 3. Cancer Res. 73(18):5730-5741.  PMCID: PMC3778117.
7.    Guzy RD, Stoilov I, Elton TJ, Mecham RP & Ornitz DM (2015) Fibroblast growth factor 2 is required for epithelial recovery, but not for pulmonary fibrosis, in response to bleomycin. Am. J. Respir. Cell Mol. Biol. 52(1):116-128.  PMCID: PMC4370255.
8.    Yin Y, Castro AM, Hoekstra M, Yan TJ, Kanakamedala AC, Dehner LP, . . . Ornitz DM (2015) Fibroblast Growth Factor 9 Regulation by MicroRNAs Controls Lung Development and Links DICER1 Loss to the Pathogenesis of Pleuropulmonary Blastoma. PLoS Genet 11(5):e1005242.  PMCID: PMC4433140.
9.    Yin Y, Ren X, Smith C, Guo Q, Malabunga M, Guernah I, . . . Ornitz DM (2016) Inhibition of fibroblast growth factor receptor 3-dependent lung adenocarcinoma with a human monoclonal antibody. Dis Model Mech 9(5):563-571.  PMCID: PMC4892666.