Ornitz Biosketch

David M. Ornitz

Alumni Endowed Professor of Developmental Biology

EDUCATION/TRAINING

INSTITUTION AND LOCATIONDEGREECompletion DateFIELD OF STUDY
University of California, DavisBS06/1981Biochemistry
University of Washington, SeattlePh.D.06/1987Biochemistry
University of Washington, SeattleMD06/1988Medicine
Harvard Medical School, Bostonpostdoc1988 – 1992Molecular Genetics

A. Personal Statement

Over the past 32 years, I have led an independent research laboratory at Washington University School of Medicine that has focused on the in vivo function of Fibroblast Growth Factors (FGFs) in development, physiology, response to injury, and cancer. My laboratory has made significant contributions to cardiovascular, inner ear, pulmonary, and skeletal system biology. My laboratory has designed and engineered knockout and conditional knockout alleles, tetracycline regulatory alleles, and transgenic mouse lines for several FGF ligands and receptors, allowing us to probe gene function, understand mechanisms regulating organogenesis, model human disease, and develop genetic tools to model and test therapeutic strategies. I have also been very interested in understanding how FGF signaling pathways interact with other signaling pathways and transcription factors to coordinate complex developmental, injury response, and regenerative processes.

Beyond my research efforts, I am committed to graduate and medical student education. I have served on the MSTP committee since 2018. I have taught in the graduate-level course Developmental Biology (Bio 5352). I co-chair the Developmental Biology Research Forum and mentor undergraduate, graduate, and postdoctoral fellows. I have mentored 12 undergraduate students (high school, college, and medical), 17 PhD or MD/PhD students, and 21 postdoctoral fellows. Many of my trainees remain active in biotechnology, clinical, or basic research. In our weekly lab meetings we strive to enhance the scientific rigor of our experiments and we discuss any relevant ethical issues associated with our ongoing and proposed research.

Complete List of Published Work in MyBibliography:

https://www.ncbi.nlm.nih.gov/myncbi/david.ornitz.1/bibliography/public/

B. Positions and Honors

Positions and Employment

2008 – pres     Alumni Endowed Professor, Dept. of Developmental Biology, Washington University

2008 – 2009    Interim Head, Dept. of Developmental Biology, Washington University

2004 – 2007    Interim Head, Dept. of Molecular Biology and Pharmacology, Washington University

2002 – 2007    Alumni Endowed Professor, Dept. of Molecular Biology and Pharmacology, Washington U.

2000 – 2002    Professor, Dept. of Molecular Biology and Pharmacology, Washington University

1996 – 2000    Associate Professor, Dept. of Molecular Biology & Pharmacology, Washington University

1992 – 1996    Assistant Professor, Dept. of Molecular Biology & Pharmacology, Washington University

1988 – 1992    Postdoctoral Fellow, Dept. of Genetics, Harvard Medical School 1983 – 1987    Graduate student, Dept. of Biochemistry, University of Washington.

Other Experience and Professional Memberships

2017 – pres     American Society for Bone and Mineral Research (ASBMR)

2008 – pres     American Association for Anatomists (AAA),

1992 – pres     Society for Developmental Biology (SDB),

1987 – pres     Member: American Association for the Advancement of Science (AAAS),

2013 – 2018    Advisory Editorial Board, Development

2008 – pres     Editorial Board, Developmental Biology

2008 – pres     Associate Editor, Developmental Dynamics

Study Sections

Ad hoc reviewer for NIH-CBY-1 (1998), NIH-CDF-5 (1999), Beckman Young Investigator Program (1999-2001), Special emphasis panel, NIH HL-99-024, Genomic applications for Heart, Lung and Blood Research (2000), Special emphasis panel for NIH DC-01-00, Studies of sensory-motor functions responsive to gravity in genetically altered model systems (2001), Special emphasis panel for NIH DA-01-011, Insertional mutagenesis in the mouse (2001), Special emphasis panel for NIH NIDCD PAR-01-103 (2001), Ad hoc reviewer for NIH NIDCD, ZDC1 SRB-A (2002), NIH NCI, Cancer center site visit, Columbia University (2003), Ad hoc reviewer for NIH-BIO, Biochemistry Study Section (2003), Pathobiochemistry study section (2004), NIH NCI, internal review (2004), Ad hoc reviewer for NIH ZRG1 MDCN-A (2004), NIH ZRG1 CDD (2004), NIH Dev-2 (full member, 2005-2009), Barnes-Jewish Hospital Foundation, ICTS study section (2009, 2010), Special Emphasis Panel for NICHD ZHD1 DSR-N (52) (2011), Chair, Special Emphasis Panel for NICHD ZHD1 DSR-Y (2012), NIH LIRR study section (Ad hoc 2013, 2014, full member 2015 – 2021).

Honors

Fellow of the American Association for the Advancement of Science, AAAS

Fellow of the American Association for Anatomists, AAA

Washington University, Outstanding Faculty Mentor Award

Washington University, Distinguished Investigator Award

Washington University, Alumni Endowed Professor

American Heart Association, Established Investigator Award

Arnold and Mabel Beckman Young Investigators Award; Lucille Markey Award

Lucille Markey Award

Medical Scientist Training Program

American Heart Association, student research program

Contributions to Science

1. Discovery of a co-factor requirement for FGF – FGF receptor interaction and mapping the ligand-receptor specificity requirement for FGF – FGF receptor signaling

Early observations showed that FGFs bind to heparan sulfate, a large glycosaminoglycan on the surface of cells and in the extracellular matrix (ECM). As a postdoctoral fellow, I discovered that heparan sulfate, or the related molecule heparin, functions as a co-factor that facilitates FGF binding to and activating the FGF receptor.a,b This work and several subsequent biochemical studies from my lab opened the field of study of ECM modulation of growth factor activity. To better understand the biochemical mechanisms that regulate interactions between FGF receptors and ligands, we investigated how alternative splicing regulates receptor activity and ligand binding specificity. We discovered an alternative splice form of FGFR3 that has unique ligand binding properties for members of the FGF9 subfamily of ligands (FGFs 9, 16, and 20). The subsequent biochemical experiments focused on determining the receptor specificity of an ever-increasing number of FGF ligands. These experiments utilized binding studies to soluble receptors and mitogenic assays on cell lines that were engineered to express individual splice forms of each FGF receptor. In 1996, we published a paper that directly compared specificity of FGFs 1 through 9.c Ten years later, we compared the activity of all 18 signaling FGFs.d These two papers are highly cited, and the BaF3 cell lines that we engineered are being used in many laboratories to investigate mechanisms that regulate FGF – FGF receptor interactions in live cells.

  • a. Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell. 1991;64:841-8.
  • b. Ornitz DM, Yayon A, Flanagan JG, Svahn CM, Levi E, Leder P. Heparin Is Required for Cell-Free Binding of Basic Fibroblast Growth-Factor to a Soluble Receptor and for Mitogenesis in Whole Cells. Mol Cell Biol. 1992;12(1):240-7 PubMed: PMIDWOS:A1992GW05300026.
  • c. Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao GX, Goldfarb M. Receptor specificity of the fibroblast growth factor family. J Biol Chem. 1996;271(25):15292-7 PubMed: PMIDWOS:A1996UT10600094.
  • d. Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem. 2006;281(23):15694-700 PMCID: 2080618.
2. Understanding mechanisms of FGFR3 mutations in Achondroplasia and FGF signaling in skeletal development and homeostasis.

Towards the beginning of my career at Washington University, a mutation in FGFR3 was discovered as the etiology of Achondroplasia, the most common form of dwarfism in humans. Subsequently, mutations in FGFR1 and FGFR2 were found to cause many of the craniosynostosis syndromes. My laboratory pursued biochemical studies where we showed that the Achondroplasia, and related Thanatophoric dysplasia mutations activate FGFR3.a This was the first example of an activating mutation in a growth factor receptor leading to decreased growth. We confirmed this prediction by engineering a mouse that overexpressed the mutant FGFR3 in chondrocytes. This work led to the concept that FGFR3 negatively regulates chondrocyte proliferation and has been the basis for many of the therapies that are currently being developed to treat Achondroplasia. We then engineered a mouse knockout for FGFR3. This mouse developed a skeletal overgrowth phenotype, opposite to that of Achondroplasia, and also had a deafness phenotype due to failure of differentiation of a specialized supporting cell (pillar cell) in the organ of Corti in the inner ear.b Our mouse model for Achondroplasia has been used by academic labs and pharmaceutical companies to develop a peptide-based drug (derivative of CNP) that is now in clinical trials for the treatment of Achondroplasia.

My laboratory has also investigated mechanisms by which FGFs and FGFRs regulate limb bud, palate, and skeletal development. We showed that FGFR1 and FGFR2 are important for osteoprogenitor development and for regulating molecules that signal to the growth plate.c Current studies are aimed at investigating the mechanisms by which FGFR signaling regulates bone growth, homeostasis, and injury response.d

  • a. Naski MC, Wang Q, Xu J, Ornitz DM. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet. 1996;13(2):233-7 PubMed: PMID8640234.
  • b. Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet. 1996;12(4):390-7 PubMed: PMID8630492.
  • c. Karuppaiah K, Yu K, Lim J, Chen J, Smith C, Long F, Ornitz DM. FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth. Development. 2016;143(10):1811-22 PMCID: PMC4874483.
  • d. 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;in press. PMID: 31206783.
3. Discovery of a role for FGF9 in lung mesenchyme development roles for FGF signaling in lung fibrosis and cancer.

After cloning the mouse Fgf9 cDNA, my laboratory demonstrated that Fgf9 is expressed in lung epithelium and mesothelium. This observation led to our construction of a mouse Fgf9 knockout and the discovery that FGF9 has a major role in the regulation of lung development through regulation of lung mesenchyme. Since this initial discovery, our research has focused on the mechanisms by which FGF9 signaling regulates lung development. We have identified a feed-forward regulatory network that involves mesenchymal FGFR signaling and Wnt/β-catenin signaling. We have generated mice that allow cell autonomous (TRE-caFgfr1) and cell non-autonomous (TRE-Fgf9) activation of FGF signaling. Using these inducible mouse lines, we have explored mechanisms by which FGF signaling may be involved in the pathogenesis of Pleuropulmonary Blastoma, a pediatric lung sarcoma that is associated with familiar loss of function mutations in DICER1.a We have also shown that FGF9 expression in adult lung causes adenocarcinoma and that FGF9 is expressed in human non-small cell lung carcinoma, a leading cause of death in adult humans.b These developmental studies have also led to recent pathophysiological studies aimed at understanding reparative functions of FGF signaling following lung injury. Our initial findings indicate a role for FGF signaling in epithelial repair and demonstrate a cell-autonomous role for FGF signaling in pulmonary fibrosis.c,d

  • a. Yin Y, Castro AM, Hoekstra M, Yan TJ, Kanakamedala AC, Dehner LP, Hill DA, Ornitz DM. 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 PMCID: PMC4433140.
  • b. Yin Y, Betsuyaku T, Garbow JR, Miao J, Govindan R, Ornitz DM. Rapid induction of lung adenocarcinoma by fibroblast growth factor 9 signaling through FGF receptor 3. Cancer Res. 2013;73(18):5730-41 PMCID: PMC3778117.
  • c. Guzy RD, Stoilov I, Elton TJ, Mecham RP, Ornitz DM. Fibroblast growth factor 2 is required for epithelial recovery, but not for pulmonary fibrosis, in response to bleomycin. Am J Respir Cell Mol Biol. 2015;52(1):116-28 PMCID: PMC4370255.
  • d. Guzy RD, Li L, Smith C, Dorry SJ, Koo HY, Chen L, Ornitz DM. Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling. J Biol Chem. 2017. Epub 2017/05/11. doi: 10.1074/jbc.M117.791764. PMID: 28487375.
4. Discovery of a role for FGF signaling in myocardial growth and cardioprotection following ischemia-reperfusion injury.

We have studied mechanisms by which FGF signaling regulates growth of the midgestation myocardium and formation of the coronary vasculature.a We demonstrated that FGF9 signaling through FGFR1 and FGFR2 is required for both myocardial proliferation and coronary vascular development. We discovered that FGF signals promote the formation of the coronary vascular system indirectly through activation of hedgehog signaling and VEGF expression. We then showed that hedgehog signaling functions as a homeostatic factor in the adult heart to maintain the coronary vasculature and is necessary for coronary neo-vascularization following ischemic injury.b We also demonstrated that FGF10 functions in the midgestation heart to regulate migration of epicardial-derived cells into the myocardium.

Current studies aim to understand the mechanisms by which FGF2 is cardioprotective in the adult heart. We showed that FGF2 is a necessary cardioprotective factor in a clinically relevant closed-chest model for ischemia-reperfusion injury. We are now working to understand how FGF2 signaling is regulated in the adult heart, why effects of increased FGF2 expression are only seen following injury, and the identity of the cellular targets of FGF2 (cardiomyocytes, endothelial cells, smooth muscle cells, interstitial cells). To address these questions, we are inactivating FGFRs in potential FGF2 target cells (myocytes, endothelial cells, fibroblasts) and examining the physiological and pathophysiological response to in vivo ischemia reperfusion injury. Additionally, we have cell-autonomously activated FGFRs in cardiomyocytes. These studies have identified multiple cell-autonomous and cell non-autonomous roles for FGF signaling in the adult cardiovascular system and have generated a mouse model for hypertrophic cardiomyopathy.c Our most recent work shows that cell autonomous FGF signaling in endothelial cells is required for neovascularization one week after IR injury.d

  • a. Lavine KJ, Yu K, White AC, Zhang X, Smith C, Partanen J, Ornitz DM. Endocardial and epicardial derived FGF signals regulate myocardial proliferation and differentiation in vivo. Dev Cell. 2005;8(1):85-95 PubMed: PMID15621532.
  • b. Lavine KJ, Kovacs A, Ornitz DM. Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice. J Clin Invest. 2008;118(7):2404-14 PMCID: 2430494.
  • c. House SL, Wang J, Castro AM, Weinheimer C, Kovacs A, Ornitz DM. Fibroblast growth factor 2 is an essential cardioprotective factor in a closed-chest model of cardiac ischemia-reperfusion injury. Physiological reports. 2015;3(1):e12278-e PMCID: PMC4387743.
  • d. House SL, Castro AM, Lupu TS, Weinheimer C, Smith C, Kovacs A, Ornitz DM. 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 PMCID: PMC4796602.
5. Discovery of a requirement for FGF20 signaling in regulating progenitor cell growth and differentiation in the developing inner ear, olfactory epithelium, and kidney.

We have identified FGF20 as an essential signaling molecule that regulates the development of sensory receptors in the inner ear. We generated mice that lack Fgf20 and showed that these mice are viable and healthy, but congenitally deaf.a Studies of cochlear development showed that FGF20 is required for sensory epithelial differentiation in the cochlea. Specifically, we showed that exposure to FGF20 must occur at a specific time during development to initiate differentiation of cells in the lateral cochlear compartment (outer hair and supporting cells). In the absence of FGF20, lateral compartment cells remain undifferentiated, postmitotic, and unresponsive to mechanisms that regulate the final stages of sensory cell differentiation. These studies suggest that mutations in FGF20 may result in deafness in humans and that FGF20 may be an important factor for the repair or regeneration of sensory cells in the inner ear. We next investigated mechanisms by which FGF9 and FGF20 cooperate to regulate the number of epithelial progenitor cells in the cochlea.b and to determine whether induction of FGF signaling can improve cochlear response to injury and facilitate regeneration.c

Recent work has identified an FGF20 expressing olfactory epithelial progenitor cell that gives rise to essentially all of the olfactory sensory epithelium.d Collectively these studies have identified FGF20 as a critical gene expressed in a variety of progenitor cell populations.

  • a. Huh SH, Jones J, Warchol ME, Ornitz DM. Differentiation of the lateral compartment of the cochlea requires a temporally restricted FGF20 signal. PLoS Biol. 2012;10(1):e1001231 PMCID: PMC3250500.
  • b. Huh SH, Warchol ME, Ornitz DM. Cochlear progenitor number is controlled through mesenchymal FGF receptor signaling. Elife. 2015;4:1-17 PMCID: PMC4434254.
  • c. 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. PMID: 31276493.
  • d. Yang LM, Huh SH, Ornitz DM. FGF20-Expressing, Wnt-Responsive Olfactory Epithelial Progenitors Regulate Underlying Turbinate Growth to Optimize Surface Area. Dev Cell. 2018;46(5):564-80 e5 PMID30100263.