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.
Wang
Qing
Q
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis 63110, USA.
Bardgett
Mark E
ME
Wong
Michael
M
Wozniak
David F
DF
Lou
Junyang
J
McNeil
Benjamin D
BD
Chen
Chen
C
Nardi
Anthony
A
Reid
David C
DC
Yamada
Kelvin
K
Ornitz
David M
DM
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