RT Journal Article
SR Electronic
T1 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
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 12339
OP 12350
DO 10.1523/JNEUROSCI.3573-06.2006
VO 26
IS 47
A1 Y. Kaga
A1 W. J. Shoemaker
A1 M. Furusho
A1 M. Bryant
A1 J. Rosenbluth
A1 S. E. Pfeiffer
A1 L. Oh
A1 M. Rasband
A1 C. Lappe-Siefke
A1 K. Yu
A1 D. M. Ornitz
A1 K.-A. Nave
A1 R. Bansal
YR 2006
UL http://www.jneurosci.org/content/26/47/12339.abstract
AB 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 ∼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.