title: Mice with conditional inactivation of fibroblast growth factor receptor-2 signaling in oligodendrocytes have normal myelin but display dramatic hyperactivity when combined with Cnp1 inactivation.
abstract: Fibroblast growth factor receptors (Fgfr) comprise a widely expressed family of developmental regulators implicated in oligodendrocyte (OL) maturation of the CNS. Fgfr2 is expressed by OLs in myelinated fiber tracks. In vitro, Fgfr2 is highly upregulated during OL terminal differentiation, and its activation leads to enhanced growth of OL processes and the formation of myelin-like membranes. To investigate the in vivo function of Fgfr2 signaling by myelinating glial cells, we inactivated the floxed Fgfr2 gene in mice that coexpress Cre recombinase (cre) as a knock-in gene into the OL-specific 2',3'-cyclic nucleotide phosphodiesterase (Cnp1) locus. Surprisingly, no obvious defects were detected in brain development of these conditional mutants, including the number of OLs, the onset and extent of myelination, the ultrastructure of myelin, and the expression level of myelin proteins. However, unexpectedly, a subset of these conditional Fgfr2 knock-out mice that are homozygous for cre and therefore are also Cnp1 null, displayed a dramatic hyperactive behavior starting at approximately 2 weeks of age. This hyperactivity was abolished by treatment with dopamine receptor antagonists or catecholamine biosynthesis inhibitors, suggesting that the symptoms involve a dysregulation of the dopaminergic system. Although the molecular mechanisms are presently unknown, this novel mouse model of hyperactivity demonstrates the potential involvement of OLs in neuropsychiatric disorders, as well as the nonpredictable role of genetic interactions in the behavioral phenotype of mice.
authors.affiliation: Department of Neuroscience, University of Connecticut Medical School, Farmington, Connecticut 06030, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kaga
authors.forename: W J
authors.initials: WJ
authors.lastname: Shoemaker
authors.forename: M
authors.initials: M
authors.lastname: Furusho
authors.forename: M
authors.initials: M
authors.lastname: Bryant
authors.forename: J
authors.initials: J
authors.lastname: Rosenbluth
authors.forename: S E
authors.initials: SE
authors.lastname: Pfeiffer
authors.forename: L
authors.initials: L
authors.lastname: Oh
authors.forename: M
authors.initials: M
authors.lastname: Rasband
authors.forename: C
authors.initials: C
authors.lastname: Lappe-Siefke
authors.forename: K
authors.initials: K
authors.lastname: Yu
authors.forename: D M
authors.initials: DM
authors.lastname: Ornitz
authors.forename: K-A
authors.initials: KA
authors.lastname: Nave
authors.forename: R
authors.initials: R
authors.lastname: Bansal
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000172:deficiency / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006948:Hyperkinesis / Q000235:genetics* / Q000503:physiopathology*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism / Q000648:ultrastructure; D009836:Oligodendroglia / Q000378:metabolism* / Q000648:ultrastructure; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018492:Dopamine Antagonists; D004676:Myelin Basic Protein; D016222:Fibroblast Growth Factor 2; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases