David M. Ornitz, M.D., Ph.D.

Alumni Endowed Professor
Developmental Biology

Developmental, Regenerative and Stem Cell Biology Program
Molecular Cell Biology Program
Neurosciences Program

  • 314-362-3908

  • 314-362-5074

  • 314-362-7058

  • 3905 South Building

  • dornitz@wustl.edu

  • http://ornitzlab.wustl.edu

  • cell signaling; development; fibroblast growth factors; mouse models; stem cells, regeneration; pulmonary hypertension; alveologenesis; endocrine signaling

  • Regulation of lung, skeletal, and cardiovascular development, injury response, and regeneration by Fibroblast Growth Factors

Research Abstract:

The Ornitz laboratory studies the in vivo functions of Fibroblast Growth Factors (FGFs) and their interactions with other signaling pathways. We use engineered mouse models and organ/cell culture to study mechanisms of organogenesis. We apply our knowledge of development to understand how growth factors regulate tissue homeostasis, and how reactivation of developmental programs function in tissue regeneration and injury response.
Respiratory system: We are investigating how FGF signaling pathways regulate postnatal alveologenesis, a process that is critical for maturation of a functional gas exchange organ. Defects in alveologenesis occur in premature birth and bronchopulmonary dysplasia. We also study the mechanisms by which FGFs are protective in lung epithelial repair in response to injury.
Pulmonary hypertension: We are investigating how FGF signaling in endothelial cells and vascular smooth muscle is protective for hypoxia-induced pulmonary hypertension, a potentially fatal condition that affects premature infants.
Skeletal system: We are investigating how FGF signaling regulates osteoblast and osteocyte function and homeostasis during postnatal bone growth and aging. We are also investigating how FGF signaling in the skeletal vasculature regulates postnatal bone growth and joint homeostasis.
Endocrine FGF function: We are investigating a rare insulin resistance syndrome, Insulin-mediated pseudoacromegaly (IMPA), that leads to overgrowth and tall stature. Sequencing an IMPA patient identified mutations in Fibroblast Growth Factor Receptor 1 (FGFR1) and β-Klotho (KLB), which form the receptor complex for FGF21, an endocrine hormone that promotes insulin sensitivity in adipose tissue by increasing glucose uptake and suppressing lipolysis.
Cardiovascular system: We are investigating the function of FGF receptor signaling in myocyte and non-myocyte cardiovascular lineages in response to ischemia-reperfusion injury.

Selected Publications:

1. Yin Y, Castro AM, Hoekstra M, Yan TJ, Kanakamedala AC, Dehner LP, et al. Fibroblast Growth Factor 9 Regulation by MicroRNAs Controls Lung Development and Links DICER1 Loss to the Pathogenesis of Pleuropulmonary Blastoma. PLoS Genet. 2015;11(5):e1005242. doi: 10.1371/journal.pgen.1005242. PubMed PMID: 25978641; PubMed Central PMCID: PMCPMC4433140.

2. House SL, Castro AM, Lupu TS, Weinheimer C, Smith C, Kovacs A, et al. Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2016;310(5):H559-71. Epub 2016/01/10. doi: 10.1152/ajpheart.00758.2015. PubMed PMID: 26747503; PubMed Central PMCID: PMCPMC4796602.

3. Karuppaiah K, Yu K, Lim J, Chen J, Smith C, Long F, et al. FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth. Development. 2016;143(10):1811-22. Epub 2016/04/08. doi: 10.1242/dev.131722. PubMed PMID: 27052727; PubMed Central PMCID: PMCPMC4874483.

4. Guzy RD, Li L, Smith C, Dorry SJ, Koo HY, Chen L, et al. Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling. J Biol Chem. 2017;292(25):10364-78. Epub 2017/05/11. doi: 10.1074/jbc.M117.791764. PubMed PMID: 28487375; PubMed Central PMCID: PMCPMC5481550.

5. Koo HY, El-Baz LM, House S, Cilvik SN, Dorry SJ, Shoukry NM, et al. Fibroblast growth factor 2 decreases bleomycin-induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation. J Pathol. 2018;246(1):54-66. Epub 2018/06/07. doi: 10.1002/path.5106. PubMed PMID: 29873400; PubMed Central PMCID: PMCPMC6175645.

6. Oladipupo SS, Kabir AU, Smith C, Choi K, Ornitz DM. Impaired tumor growth and angiogenesis in mice heterozygous for Vegfr2 (Flk1). Sci Rep. 2018;8(1):14724. Epub 2018/10/05. doi: 10.1038/s41598-018-33037-2. PubMed PMID: 30283071; PubMed Central PMCID: PMCPMC6170482.

7. McKenzie J, Smith C, Karuppaiah K, Langberg J, Silva MJ, Ornitz DM. Osteocyte Death and Bone Overgrowth in Mice Lacking Fibroblast Growth Factor Receptors 1 and 2 in Mature Osteoblasts and Osteocytes. J Bone Miner Res. 2019;34(9):1660-75. Epub 2019/06/18. doi: 10.1002/jbmr.3742. PubMed PMID: 31206783; PubMed Central PMCID: PMCPMC6744314.

8. Yang LM, Cheah KSE, Huh SH, Ornitz DM. Sox2 and FGF20 interact to regulate organ of Corti hair cell and supporting cell development in a spatially-graded manner. PLoS Genet. 2019;15(7):e1008254. Epub 2019/07/06. doi: 10.1371/journal.pgen.1008254. PubMed PMID: 31276493; PubMed Central PMCID: PMCPMC6636783.

9. Hagan AS, Zhang B, Ornitz DM. Identification of a FGF18-expressing alveolar myofibroblast that is developmentally cleared during alveologenesis. Development. 2020;147(2):dev.181032. Epub 2019/12/22. doi: 10.1242/dev.181032. PubMed PMID: 31862844; PubMed Central PMCID: PMCPMC6983722.

10. Yin Y, Ornitz DM. FGF9 and FGF10 activate distinct signaling pathways to direct lung epithelial specification and branching. Sci Signal. 2020;13(621):eaay4353. Epub 2020/03/05. doi: 10.1126/scisignal.aay4353. PubMed PMID: 32127497.

Last Updated: 6/30/2020 4:38:08 PM

Developing mouse lung showing proximal SOX2 expressing epithelium in red and distal SOX9 expressing epithelium in green. The proximal-distal distribution of these markers of epithelial differentiation are regulated by FGF9 signaling.
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