Eiraku, M. et al. DNER acts as a neuron-specific Notch ligand during Bergmann glial development. Nature Neurosci. 8, 873-880

Department of Biophysics, Kyoto University, Kioto, Kyōto, Japan
Nature Neuroscience (Impact Factor: 16.1). 08/2005; 8(7):873-80. DOI: 10.1038/nn1492
Source: PubMed


Differentiation of CNS glia is regulated by Notch signaling through neuron-glia interaction. Here, we identified Delta/Notch-like EGF-related receptor (DNER), a neuron-specific transmembrane protein, as a previously unknown ligand of Notch during cellular morphogenesis of Bergmann glia in the mouse cerebellum. DNER binds to Notch1 at cell-cell contacts and activates Notch signaling in vitro. In the developing cerebellum, DNER is highly expressed in Purkinje cell dendrites, which are tightly associated with radial fibers of Bergmann glia expressing Notch. DNER specifically binds to Bergmann glia in culture and induces process extension by activating gamma-secretase- and Deltex-dependent Notch signaling. Inhibition of Deltex-dependent, but not RBP-J-dependent, Notch signaling in Bergmann glia suppresses formation and maturation of radial fibers in organotypic slice cultures. Additionally, deficiency of DNER retards the formation of radial fibers and results in abnormal arrangement of Bergmann glia. Thus, DNER mediates neuron-glia interaction and promotes morphological differentiation of Bergmann glia through Deltex-dependent Notch signaling.

Download full-text


Available from: Katsuhiko Ono, Oct 28, 2015
  • Source
    • "For example, expression of an activated form of Notch in the retina leads to an increase in cells expressing Müller glial markers [13]. Similarly in the forebrain Notch promotes the acquisition of a radial glial phenotype [14]; while in the cerebellum, loss of a novel Notch ligand (DNER) or Jagged1 leads to defects in Bergmann glial differentiation [15], [16]. However, whether Notch can play an instructive role in non-glial cell fates, such as the supporting cells of the inner ear, is not known. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose To determine whether activated Notch can promote a supporting cell fate during sensory cell differentiation in the inner ear. Methods An activated form of the Notch1 receptor (NICD) was expressed in early differentiating hair cells using a Gfi1-Cre mouse allele. To determine the effects of activated Notch on developing hair cells, Gfi1-NICD animals and their littermate controls were assessed at 5 weeks for hearing by measuring auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). The differentiation of NICD-expressing hair cells was assessed at postnatal day (P) 6, 11 and 20, using histological and molecular markers for hair cells, as well as supporting cells/progenitor cells. We also examined whether the effects of Notch were mediated by SOX2, a gene expressed in supporting cells and a likely downstream target of Notch, by crossing an inducible form of SOX2 to the Gfi1-Cre. Results Activation of Notch1 in developing auditory hair cells causes profound deafness. The NICD-expressing hair cells switch off a number of hair cell markers and lose their characteristic morphology. Instead, NICD-expressing hair cells adopt a morphology resembling supporting cells and upregulate a number of supporting cell markers. These effects do not appear to be mediated by SOX2, because although expression of SOX2 caused some hearing impairment, the SOX2-expressing hair cells did not downregulate hair cell markers nor exhibit a supporting cell-like phenotype. Conclusions Our data show that Notch signaling inhibits hair cell differentiation and promotes a supporting cell-like phenotype, and that these effects are unlikely to be mediated by SOX2.
    Full-text · Article · Sep 2014 · PLoS ONE
  • Source
    • "One of the major functions of Notch signaling is its ability to influence cell fate decisions during development (Kwon et al., 2005). Several of the Notch pathway components have been linked to the vascular system development, including Jagged1, Notch1, Notch2, Notch4 and presenilin (Eiraku et al., 2005;Bray et al., 2008). The Notch1 receptor is responsible for the blockade of cardiogenesis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: miRNAs have been found to play a major role in cardiomyopathy, a heart muscle disorder characterized by cardiac dysfunction. Several miRNAs including those involved in heart development are found to be dysregulated in cardiomyopathy. These miRNAs act either directly or indirectly by controlling the genes involved in normal development and functioning of the heart. Indirectly it also targets modifier genes and genes involved in signaling pathways. In this review, miRNAs involved in heart development, including dysregulation of miRNA which regulate various genes, modifiers and notch signaling pathway genes leading to cardiomyopathy are discussed. A study of these miRNAs would give an insight into the mechanisms involved in the processes of heart development and disease. Apart from this, information gathered from these studies would also generate suitable therapeutic targets in the form of antagomirs which are chemically engineered oligonucleotides used for silencing miRNAs.
    Preview · Article · Nov 2013 · EXCLI Journal
  • Source
    • "Recently, the Delta/Notch-like EGF-related receptor (DNER) has been identified as a Notch ligand that is expressed on Purkinje cells. DNER-deficient mice display disorganization of BG fibers, as well as the ectopic localization of BG [14], however, abnormal BG development in DNER-deficient mice became less significant by postnatal week 3 and had improved by the adult stages, which suggests that DNER-Notch signaling is only important for the maturation of BG in the early developmental stages. Taken together, these findings suggest that Dll1-Notch signaling is required for BG monolayer formation, whereas Jagged 1-Notch or DNER-Notch signaling is not crucial for BG arrangement. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Bergmann glia (BG) are unipolar cerebellar astrocytes. The somata of mature BG reside in the Purkinje cell layer and extend radially arranged processes to the pial surface. BG have multiple branched processes, which enwrap the synapses of Purkinje cell dendrites. They migrate from the ventricular zone and align next to the Purkinje cell layer during development. Previously, we reported that Notch1, Notch2, and RBPj genes in the BG play crucial roles in the monolayer formation and morphogenesis of BG. However, it remains to be determined which ligand activates Nocth1 and Notch 2 on BG. Delta-like 1 (Dll1) is a major ligand of Notch receptors that is expressed in the developing cerebellum. Results In this study, we used human glial fibrillary acidic protein (hGFAP) promoter-driven Cre-mediated recombination to delete Dll1 in BG. Dll1-conditional mutant mice showed disorganization of Bergmann fibers, ectopic localization of BG in the molecular layer and a reduction in the number of BG. Conclusion These results suggest that Dll1 is required for the formation of the BG layer and its morphological maturation, apparently through a Notch1/2-RBPj dependent signaling pathway.
    Full-text · Article · May 2013 · Molecular Brain
Show more