Biographical Sketch

NAME: Ornitz, David M.

POSITION TITLE: Alumni Endowed Professor of Developmental Biology
EDUCATION/TRAINING
INSTITUTION AND LOCATION DEGREE Completion Date FIELD OF STUDY
University of California, Davis BS 06/1981 Biochemistry
University of Washington, Seattle Ph.D 06/1987 Biochemistry
University of Washington, Seattle MD 06/1988 Medicine
Harvard Medical School, Boston postdoc 1988 – 1992 Molecular Genetics

A.        Personal Statement

As a graduate student in the MD-PhD program at the University of Washington, I was at the forefront of developing transgenic mouse technology for in vivo models of cancer and as tools to identify transcriptional regulatory elements. As a postdoctoral fellow in the Department of Genetics at Harvard Medical School, I developed a binary genetic system to model cancer and other lethal diseases in mice. I also discovered that heparan sulfate proteoglycans are required for Fibroblast Growth Factor (FGF) signaling. This discovery linked cell-surface and extracellular matrix molecules to growth factor signaling pathways. Over the past 24 years, I have led an independent research laboratory at Washington University School of Medicine. My research has primarily focused on the in vivo function of 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, regenerative processes, and cancer.

Lung development and injury response has been a focus of my lab for over 15 years. I interact with the Division of Pulmonary Medicine at Washington University. I have recently trained a physician scientist pulmonary fellow, Dr. Robert Guzy, who has now started his own laboratory at the University of Chicago. I am also consulting on a project led by Dr. Steve Brody in the Division of Pulmonary Medicine. I have interacted with the Cardiovascular Division at Washington University for over 10 years. I am an adjunct member of the Center for Cardiovascular Research (CCR). I also serve on the Steering Committee for the T32 postdoctoral Cardiovascular Research Training Program (T32 HL007081). My laboratory has studied FGF signaling in heart development and more recently focused on FGF signaling in cardiac and vascular response to injury. My laboratory interacts extensively with the Washington University Mouse Cardiovascular Phenotyping Core (MCPC) for ischemia-reperfusion injury studies using our FGF and FGF receptor conditional mutant mice.

In addition to my research efforts, I am committed to graduate and medical student education. I teach in the graduate-level courses Advanced Genetics (Bio 5491) and Developmental Biology (Bio 5352), and the medical student elective course, Development and Disease (Bio 500C). I run the Developmental Biology Research Forum and mentor undergraduate, graduate and postdoctoral fellows. I have mentored 11 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.

B. Positions and Honors

Positions and Employment

1983 – 1987      Graduate student, Dept. of Biochemistry, University of Washington
1988 – 1992      Postdoctoral Fellow, Dept. of Genetics, Harvard Medical School
1992 – 1996      Assistant Professor, Dept. of Molecular Biology & Pharmacology, Washington University
1996 – 2000      Associate Professor, Dept. of Molecular Biology & Pharmacology, Washington University
2000 – 2002      Professor, Dept. of Molecular Biology and Pharmacology, Washington University
2002 – 2007      Alumni Endowed Professor, Dept. of Molecular Biology and Pharmacology, Washington U.
2004 – 2007      Interim Head, Dept. of Molecular Biology and Pharmacology, Washington University
2008 – 2009      Interim Head, Dept. of Developmental Biology, Washington University
2008 – pres       Alumni Endowed Professor, Dept. of Developmental Biology, Washington University

Other Experience and Professional Memberships

Member: AAAS, Society for Developmental Biology, Society for Neuroscience, and Association for Research in Otolaryngology, American Association of Anatomists, American Physiological Society
Co-director of the Siteman Cancer Center program in Cancer and Developmental Biology. 1997-2013.
Chair, Gordon Research Conference, Fibroblast growth factors in development and disease, March 2006
Chair, AAA Annual Meeting at Experimental Biology, Symposium on lung development, San Diego, 2012
Chair, 51st and 52nd Midwest Society for Developmental Biology Meeting, St. Louis, 2013, 2014
Chair, Fusion conference, Fibroblast growth factors in development and repair, February 2015
Editorial Board, Developmental Biology; Development
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 June 2013, 2014, full member: July 2015 – 2021).

Honors

American Heart Association, student research program
Medical Scientist Training Program
Arnold and Mabel Beckman Young Investigators Award
Lucille Markey Award
American Heart Association, Established Investigator Award
Washington University, Alumni Endowed Professor
Washington University, Distinguished Investigator Award
Washington University, Outstanding Faculty Mentor Award

Contributions to Science

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.

Discovery that the mutations in FGF receptor 3 that cause Achondroplasia and related disorders are gain-of-function mutations that directly decrease chondrocyte growth.

Towards the beginning of my career at Washington University, a mutation in FGFR3 was discovered to be the etiology of Achondroplasia, the most common form of dwarfism in humans. Subsequently, mutations in FGFR1 and FGFR2 were found to cause a cluster of genetic diseases called 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. 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 C-type natriuretic peptide) 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 identified two FGF ligands (FGF9 and FGF18) that are required for skeletal development.c We showed that FGFR1 and FGFR2 are important for osteoprogenitor development and for regulating molecules that signal to the growth plate.d Current studies are aimed at investigating the mechanisms by which FGFR signaling regulates bone/cartilage growth, homeostasis, and injury response. I have recently published a major review on FGFs in skeletal development.

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. Hung IH, Schoenwolf GC, Lewandoski M, Ornitz DM. A combined series of Fgf9 and Fgf18 mutant alleles identifies unique and redundant roles in skeletal development. Dev Biol. 2016;411(1):72-84 PMCID: PMC4801039.
d. 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

Discovery that FGF9 regulates lung mesenchyme development.

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.a 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.b 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.c 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 question whether FGF signaling has a direct role in pulmonary fibrosis.d

a. Yin Y, Wang F, Ornitz DM. Mesothelial- and epithelial-derived FGF9 have distinct functions in the regulation of lung development. Development. 2011;138(15):3169-77 PMCID: PMC3188607.
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. 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.
d. 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.

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.

Discovery of a requirement for FGF20 signaling in regulating progenitor cell growth and differentiation in the developing inner ear 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. Analysis of mice that lack Fgf20 and the related family member Fgf9 revealed that both ligands are required for progenitor cell growth in the CAP mesenchyme of the developing kidney.b Although mutations in the human FGF20 gene have not yet been identified in patients with hearing loss, study of Fgf9/20 double knockout mice led to the identification of a human family in which renal agenesis is associated with a mutation in FGF20. Current studies are investigating mechanisms by which FGF9 and FGF20 cooperate to regulate the number of epithelial progenitor cells in the cochleac and to determine whether induction of FGF signaling can improve cochlear response to injury and facilitate regeneration.

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. Barak H, Huh SH, Chen S, …..Ornitz DM, Kopan R. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev Cell. 2012;22(6):1191-207 PMCID: PMC3376351.
c. Huh SH, Warchol ME, Ornitz DM. Cochlear progenitor number is controlled through mesenchymal FGF receptor signaling. Elife. 2015;4:1-17 PMCID: PMC4434254.