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

Alumni Endowed Professor

Department of Developmental Biology

Developmental Biology Program
Neurosciences Program
Molecular Cell Biology Program

Research Interests 2008

Fibroblast growth factors (FGFs) are essential molecules for mammalian development and physiology. FGF signaling pathways interact with hedgehog, BMP, TGFb and Wnt signaling pathways to regulate cell proliferation, migration and differentiation. Mutations in the genes encoding FGFs and FGF receptors (FGFRs) result in embryonic lethality, developmental defects, physiological or neurological abnormalities. Additionally, gain of function mutations in FGFRs result in hereditary craniofacial and skeletal dysplasias in humans.

We are studying FGFs, FGF receptors and a variety of other interacting signaling pathways (hedgehog, Wnt, BMP, TGFb, VEGF) in mouse embryogenesis and adult mice with a focus on skeletal, cardiac, vascular and pulmonary development and physiology. Using knockout and conditional knockout technology we have constructed FGF and FGF receptor mutants with defects in these organ systems. Mutant mice are being studied as genetic and developmental model systems for mesodermal and epithelial patterning and growth, and as models for human disease.

We have recently discovered that a subfamily of FGFs acts intracellularly (iFGF) in neurons and are important for neuronal signal transduction. Disruption of the intracellular signaling molecule, FGF14 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/FHF4 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.
We are also investigating the function of a novel multi-transmembrane domain protein family, the Otopetrins. Otopetrin1 was initially identified by positional cloning of the tilted mouse. We hypothesize that this family of proteins functions as a channel, transporter, or a regulator involved in controlling the contents or function of exocytotic vesicles that may contribute to structures required for extracellular mineralization. In recent studies we have shown that Otopetrin1 is a novel regulator of intracellular calcium and functions to regulate extracellular calcium flux in response to purinergic stimuli.

• Keywords: Development, neurobiology, bone biology, cell signaling, growth factors

Hughes, I., Saito, M., Schlesinger, P.H., and Ornitz, D.M. (2007). Otopetrin1 activation by purinergic nucleotides regulates intracellular calcium. Proc Natl Acad Sci U S A 104, 12023-12028.

Hung, I.H., Yu, K., Lavine, K.J., and Ornitz, D.M. (2007). FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod
. Dev Biol 307, 300-313.

Laezza, F., Gerber, B.R., Lou, J., Kozel, M.A., Hartman, H., Craig, A.M., Ornitz, D.M., and Nerbonne, J.M. (2007). The Fgf14(F145S) mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability. J Neurosci 27, 12033-12044.

White, A.C., Lavine, K.J., and Ornitz, D.M. (2007). FGF9 and SHH Regulate Mesenchymal Vegfa Expression and Development of the Pulmonary Capillary Network. Development 134, 3743-3752.

Yu, K., and Ornitz, D.M. (2008). FGF signaling regulates mesenchymal differentiation and skeletal patterning along the limb bud proximodistal axis. Development 135, 483-491.

Ten word research description:

FGFs in lung, skeletal, cardiovascular and CNS development and function.