Impaired cerebellar functions in mutant mice lacking DNER.
DNER is a transmembrane protein carrying extracellular EGF repeats and is strongly expressed in Purkinje cells (PCs) in the cerebellum. Current study indicated that DNER functions as a new Notch ligand and mediates the functional communication via cell-cell interaction. By producing and analyzing knockout mice lacking DNER, we demonstrate its essential roles in functional and morphological maturation of the cerebellum. The knockout mice exhibited motor discoordination in the fixed bar and rota-rod tests. The cerebellum from the knockout mice showed significant retardation in morphogenesis and persistent abnormality in fissure organization. Histochemical and electrophysiological analyses detected that PCs retained multiple innervations from climbing fibers (CFs) in the mutant cerebellum. Synaptic transmission from parallel fibers (PFs) or CFs to PCs was apparently normal, while glutamate clearance at the PF-PC synapses was significantly impaired in the mutant mice. Moreover, the protein level of GLAST, the glutamate transporter predominantly expressed in Bergmann glia (BG), was reduced in the mutant cerebellum. Our results indicate that DNER takes part in stimulation of BG maturation via intercellular communication and is essential for precise cerebellar development.
Tohgo
Akira
A
Department of Medical Chemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
Eiraku
Mototsugu
M
Miyazaki
Taisuke
T
Miura
Eriko
E
Kawaguchi
Shin-Ya
SY
Nishi
Miyuki
M
Watanabe
Masahiko
M
Hirano
Tomoo
T
Kengaku
Mineko
M
Takeshima
Hiroshi
H
D000818:Animals; D002454:Cell Differentiation; D002531:Cerebellum / Q000033:anatomy & histology / Q000254:growth & development / Q000502:physiology* / Q000503:physiopathology*; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology
C486765:Dner protein, mouse; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D018698:Glutamic Acid