Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14.
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.
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis 63110, USA.
Qing
Q
Wang
Mark E
ME
Bardgett
Michael
M
Wong
David F
DF
Wozniak
Junyang
J
Lou
Benjamin D
BD
McNeil
Chen
C
Chen
Anthony
A
Nardi
David C
DC
Reid
Kelvin
K
Yamada
David M
DM
Ornitz
D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001370:Axonal Transport / Q000235:genetics*; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D001479:Basal Ganglia / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology; D002465:Cell Movement / Q000235:genetics; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D002819:Chorea / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003042:Cocaine / Q000494:pharmacology; D018491:Dopamine Agonists / Q000009:adverse effects; D005260:Female; D005346:Fibroblast Growth Factors / Q000172:deficiency* / Q000235:genetics; D018390:Gene Targeting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D017072:Neostriatum / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D013378:Substantia Nigra / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D001616:beta-Galactosidase / Q000235:genetics
D018491:Dopamine Agonists; D016760:Proto-Oncogene Proteins c-fos; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors; D020928:Mitogen-Activated Protein Kinases; D001616:beta-Galactosidase; D003042:Cocaine