Research Abstract:
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 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 (Otop1) was initially identified by positional cloning of the tilted mouse. Tilted mice lack, otoconia, small biomineral particles that serve as mechanotransducers required for the perception of gravitational fields and linear acceleration. Using an Otop1 knockout mouse we have shown that Otop1 functions to regulate calcium in vestibular supporting cells. We are investigating possible functions of Otop1 as a novel calcium channel or transporter that regulates the calcium content of exocytotic vesicles that contribute to structures required for extracellular biomineralization.
Selected Publications:
Laezza F, Lampert A, Kozel MA, Gerber BR, Rush AM, Nerbonne JM, Waxman SG, Dib-Hajj SD and Ornitz DM. FGF14 N-Terminal Splice Variants Differentially Modulate Nav1.2 and Nav1.6-Encoded Sodium Channels. Mol Cell Neurosci. 2009 42: 90-101.
Schmid GJ, Kobayashi C, Sandell LJ and Ornitz DM. Fibroblast Growth Factor expression during skeletal fracture healing in mice. Dev Dyn 2009 238: 766-774.
Shakkottai VG, Xiao M, Xu L, Wong M, Nerbonne JM, Ornitz DM and Yamada KA. FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons. Neurobiol Dis 2009 33: 81-88.
Yin Y, White AC, Huh SH, Hilton MJ, Kanazawa H, Long F and Ornitz DM. An FGF-WNT gene regulatory network controls lung mesenchyme development. Dev Biol 2008 319: 426-436.
Lavine KJ, Kovacs A, and Ornitz DM. Hedgehog signaling is critical for maintenance of the adult coronary vasculature. J Clin Invest 2008 118: 2404-2414.
Last Updated: 09/03/2009 |