David M. Ornitz, M.D., Ph.D.
Alumni Endowed Professor
Developmental, Regenerative and Stem Cell Biology Program
Molecular Cell Biology Program
3902 South Building
cell signaling; development; fibroblast growth factors; mouse models; neurobiology; stem cells; regeneration; cancer
FGF signaling in cardiovascular, lung, skeletal, and inner ear development, injury response, and regeneration
The overall focus of my laboratory is on in vivo functions of Fibroblast Growth Factors (FGFs), their interactions with other signaling pathways, and their role in tissue regeneration, response to injury, and cancer. We use in vivo mouse models to study mechanisms of organogenesis and apply our knowledge of developmental processes to understand mechanisms regulating tissue homeostasis, and reactivation of developmental programs in oncogenesis and in tissue regeneration in response to injury.
Cardiovascular system: We are investigating the function of FGF receptor signaling in specific cardiovascular lineages. We have showed that endothelial FGF receptor signaling is essential for chemical-induced skin carcinogenesis, wound healing, and the hearts response to ischemia-reperfusion injury. FGF receptors are now being targeted in cardiomyocytes and interstitial cells of the heart and other tissues to similarly address their role in cancer, wound healing and ischemia-reperfusion injury.
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.
Skeletal system: We are investigating how FGF signaling regulates osteoblast function and bone density during development and aging. We have shown that FGF signaling in the osteoblast indirectly regulates growth plate chondrocyte proliferation and differentiation and directly regulates the metabolic activity of osteoblasts. We have also identified an autocrine FGF signal that regulates articular chondrocyte differentiation. Through these mechanisms, FGF signaling regulates longitudinal bone growth, bone density, integrity of articular cartilage.
Inner ear and olfactory development and regeneration: We have identified FGF20 as an essential signal that regulates the development of sensory receptors in the inner ear. Mice lacking FGF20 are viable, healthy and congenitally deaf. FGF20 expression also marks a progenitor cell lineage in the olfactory epithelium and functions to regulate the growth of the underlying nasal turbinates. Our aims are to identify the molecular mechanisms that regulate the expression of Fgf20 during the embryonic development of the cochlea and olfactory epithelium; to determine how FGF20 regulates sensory progenitor cell growth and the differentiation of cochlear outer hair and supporting cells in the organ of Corti; and to identify the specific genes and pathways that act downstream of FGF20 during cochlear and olfactory development using Next Gen mRNA sequencing. We are testing the hypothesis that FGF signaling can enhance sensory cell regeneration following ototoxic damage.
Neuronal regulation: We are studying a unique subfamily of FGFs that act intracellularly (iFGFs) in neurons and cardiomyocytes and that are important for regulating cell excitability through interactions with voltage gated sodium channels. Disruption of FGF14, one of four iFGFs, results in an anatomically normal mouse with severe neurobehavioral phenotypes including ataxia, seizure, paroxysmal dystonia and cognitive impairment. A mutation in FGF14 in humans is the cause of a dominant progressive spinocerebellar ataxia syndrome, SCA27. We are investigating the role of FGF14 as a regulator of neuronal excitability, the mechanism of action of the SCA27 mutation in FGF14, and the role of FGF14 as an intracellular regulator of voltage gated sodium channel function.
1. Karuppaiah K, Yu K, Lim J, Chen J, Smith C, Long F & Ornitz DM (2016) FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth. Development 143(10):1811-1822. PMCID: PMC4874483.
2. Hung IH, Schoenwolf GC, Lewandoski M & Ornitz DM (2016) A combined series of Fgf9 and Fgf18 mutant alleles identifies unique and redundant roles in skeletal development. Dev Biol 411(1):72-84. PMCID: PMC4801039.
3. House SL, Castro AM, Lupu TS, Weinheimer C, Smith C, Kovacs A & Ornitz DM (2016) Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 310(5):H559-571. PMCID: PMC4796602.
4. 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.
5. Ornitz DM & Marie PJ (2015) Fibroblast growth factor signaling in skeletal development and disease. Genes Dev. 29(14):1463-1486. PMCID: PMC4526732.
6. Huh SH, Warchol ME & Ornitz DM (2015) Cochlear progenitor number is controlled through mesenchymal FGF receptor signaling. Elife 4:1-17. PMCID: PMC4434254.
7. House SL, Wang J, Castro AM, Weinheimer C, Kovacs A & Ornitz DM (2015) Fibroblast growth factor 2 is an essential cardioprotective factor in a closed-chest model of cardiac ischemia-reperfusion injury. Physiological reports 3(1):e12278-e12278. PMCID: PMC4387743.
8. 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.
9. Oladipupo SS, Smith C, Santeford A, Park C, Sene A, Wiley LA, . . . Ornitz DM (2014) Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis. Proc Natl Acad Sci U S A 111(37):13379-13384. PMCID: PMC4169958.
10. Huh SH, Jones J, Warchol ME & Ornitz DM (2012) Differentiation of the lateral compartment of the cochlea requires a temporally restricted FGF20 signal. PLoS Biol 10(1):e1001231. PMCID: PMC3250500.
Last Updated: 8/25/2016 11:59:03 AM
Cochlea from a postnatal day 4 mouse lacking the Fgf20 gene showing a malformed sensory epithelium that is interrupted by patches of undifferentiated epithelial cells. Fgf20 knockout mice are viable and healthy, but have profound hearing loss.?