Principal Investigator: David Ornitz (WashU Developmental Biology)
Co-investigators: Kel Yamada (formerly WashU Neurology), Jeanne Nerbonne (WashU Developmental Biology), David Wozniak (WashU Psychiatry)
Patients with spinocerebellar ataxias (SCAs) experience a loss of muscle control in their arms and legs, with resulting loss of balance and coordination. Patients with SCA type 27, a dominantly-inherited condition, have progressive ataxia as well as mental retardation. SCA27 is caused by a single-gene mutation in the gene encoding fibroblast growth factor 14 (FGF14). An animal model lacking FGF14 function shows similar behavior. This project will fully characterize the degenerative phenotype in FGF14-deficient animals. Additionally, these investigators will generate an animal model which more closely resembles the genetics of the human disease, to reveal the molecular mechanisms which lead from FGF14 mutation to degeneration of cerebellar neurons.
“FGF14 in the regulation of Purkinje neuron excitability and SCA27“
NIH-NINDS, R01NS065761-01 (PI, Ornitz)
The molecular, cellular and physiological studies proposed will provide new and fundamentally important insights into the functional roles of FGF14 in regulating neuronal excitability and into the underlying molecular mechanisms by which mutations in FGF14 cause disease in humans.
FGF14 mutant mouse, SCA27
Laezza, F., Lampert, A., Kozel, M.A., Gerber, B.R., Rush, A.M., Nerbonne, J.M., Waxman, S.G., Dib-Hajj, S.D., and Ornitz, D.M. FGF14 N-Terminal Splice Variants Differentially Modulate Nav1.2 and Nav1.6-Encoded Sodium Channels. Mol Cell Neurosci 42, 90-101, (2009).
Shakkottai, V.G., Xiao, M., Xu, L., Wong, M., Nerbonne, J.M., Ornitz, D.M., and Yamada, K.A. FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons. Neurobiol Dis 33, 81-88, (2009).
Xiao, M., Bosch, M.K., Nerbonne, J.M., and Ornitz, D.M. FGF14 localization and organization of the axon initial segment. Mol Cell Neurosci 56, 393-403, (2013).
Bosch MK, Nerbonne JM, Ornitz DM. Dual transgene expression in murine cerebellar Purkinje neurons by viral transduction in vivo. PLoS One. 9(8):e104062, (2014).
Bosch MK, Carrasquillo Y, Ransdell JL, Kanakamedala A, Ornitz DM, Nerbonne JM. Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance. J Neurosci.; 35(17):6752-69, (2015).
Bosch MK, Nerbonne JM, Townsend RR, Miyazaki H, Nukina N, Ornitz DM, Marionneau C. Proteomic analysis of native cerebellar iFGF14 complexes. Channels (Austin, Tex).;10(4):297-312, (2016).
Updated June 2017