Project 1: Regulation of Neuronal Excitability by intracellular FGFs.
We are studying a unique subfamily of Fibroblast Growth Factors that act intracellularly (iFGFs) in neurons and cardiomyocytes and are important for regulating cell excitability. 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.
Project 2: Regulation of cochlear development and regeneration by Fibroblast Growth Factor 20.
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. Our aims are to identify the molecular mechanisms that regulate the expression of Fgf20 during the embryonic development of the cochlea; to determine how FGF20 regulates 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 development using Next Gen mRNA sequencing. Such knowledge will be essential to promote therapeutic repair and regeneration of lost or damaged sensory receptors in the inner ear.
Research Photos (Click to Enlarge)
Research Publications
Shakkottai VG, Xiao M, Xu L, Wong M, Nerbonne JM, Ornitz DM, Yamada KA (2009 Jan). FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons. Neurobiol Dis. 33 (1): 81-8. Full Article >
Laezza F, Lampert A, Kozel MA, Gerber BR, Rush AM, Nerbonne JM, Waxman SG, Dib-Hajj SD, Ornitz DM (2009 Oct). FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels. Mol Cell Neurosci. 42 (2): 90-101. Full Article >
Xiao M, Xu L, Laezza F, Yamada K, Feng S, Ornitz DM (2007 Mar). Impaired hippocampal synaptic transmission and plasticity in mice lacking fibroblast growth factor 14. Mol Cell Neurosci. 34 (3): 366-77. Full Article >
Laezza F, Gerber BR, Lou JY, Kozel MA, Hartman H, Craig AM, Ornitz DM, Nerbonne JM (2007 Oct 31). The FGF14(F145S) mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability. J Neurosci. 27 (44): 12033-44. Full Article >
Kim E, Hyrc KL, Speck J, Lundberg YW, Salles FT, Kachar B, Goldberg MP, Warchol ME, Ornitz DM (2010 Dec). Regulation of cellular calcium in vestibular supporting cells by otopetrin 1. J Neurophysiol. 104 (6): 3439-50. Full Article >
Yin Y, Wang F, Ornitz DM (2011 Aug). Mesothelial- and epithelial-derived FGF9 have distinct functions in the regulation of lung development. Development. 138 (15): 3169-77. Full Article >
Contact Info
David Ornitz, M.D., Ph.D.
Office Location: 3902 South Bldg.
Office Phone: 314-362-3908
Lab Phone: 314-362-5074
Campus Box: 8103
Fax: 314-362-7058
dornitz@wustl.edu
http://devbio.wustl.edu/ornitzlab/Index.htm
