Abstract
Fibroblast growth factor 14 (FGF14) belongs to a distinct subclass of FGFs that is expressed in the developing and adult CNS. We disrupted the Fgf14 gene and introduced an Fgf14(N-beta-Gal) allele that abolished Fgf14 expression and generated a fusion protein (FGF14N-beta-gal) containing the first exon of FGF14 and beta-galactosidase. Fgf14-deficient mice were viable, fertile, and anatomically normal, but developed ataxia and a paroxysmal hyperkinetic movement disorder. Neuropharmacological studies showed that Fgf14-deficient mice have reduced responses to dopamine agonists. The paroxysmal hyperkinetic movement disorder phenocopies a form of dystonia, a disease often associated with dysfunction of the putamen. Strikingly, the FGF14N-beta-gal chimeric protein was efficiently transported into neuronal processes in the basal ganglia and cerebellum. Together, these studies identify a novel function for FGF14 in neuronal signaling and implicate FGF14 in axonal trafficking and synaptosomal function.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Ataxia / genetics
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Ataxia / metabolism*
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Ataxia / physiopathology
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Axonal Transport / genetics*
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Axons / metabolism*
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Axons / pathology
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Basal Ganglia / growth & development
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Basal Ganglia / metabolism
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Basal Ganglia / physiopathology
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Brain / growth & development
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Brain / metabolism*
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Brain / physiopathology
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Cell Movement / genetics
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Cerebellum / growth & development
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Cerebellum / metabolism
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Cerebellum / physiopathology
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Chorea / genetics
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Chorea / metabolism*
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Chorea / physiopathology
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Cocaine / pharmacology
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Dopamine Agonists / adverse effects
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Female
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Fibroblast Growth Factors / deficiency*
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Fibroblast Growth Factors / genetics
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Gene Targeting
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Male
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / metabolism
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Neostriatum / growth & development
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Neostriatum / metabolism
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Neostriatum / physiopathology
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Proto-Oncogene Proteins c-fos / drug effects
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Proto-Oncogene Proteins c-fos / metabolism
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Substantia Nigra / growth & development
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Substantia Nigra / metabolism
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Substantia Nigra / physiopathology
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beta-Galactosidase / genetics
Substances
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Dopamine Agonists
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Proto-Oncogene Proteins c-fos
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fibroblast growth factor 14
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Fibroblast Growth Factors
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Mitogen-Activated Protein Kinases
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beta-Galactosidase
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Cocaine