DNER acts as a neuron-specific Notch ligand during Bergmann glial development

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.

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    • "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. "
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    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.
    PLoS ONE 09/2014; 9(9):e108160. DOI:10.1371/journal.pone.0108160 · 3.23 Impact Factor
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    • "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. "
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    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.
    Molecular Brain 05/2013; 6(1):25. DOI:10.1186/1756-6606-6-25 · 4.90 Impact Factor
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    • "Targeted MEKK1 degradation by Deltex suppresses the activation of T-cells [16]. In mice, three new ligands to the Notch receptor family have been identified which signal specifically through the DTX1 pathway [17]-[19] independently of RBPJκ and MAML1 and one of these ligands (DNER) has been implicated in non-canonical regulation of glioma inducing cells [20]. However, the genes involved in this pathway remain ill-defined [21], [22]. "
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    ABSTRACT: (GBM) is a highly malignant primary tumor of the central nervous system originating in glial cells. GBM results in more years of life lost than any other cancer type. Low levels of Notch receptor expression correlates with prolonged survival in various high grade gliomas independent of other markers. Different downstream pathways of Notch receptors have been identified. We tested if the Notch/Deltex pathway, which is distinct from the canonical, CSL-mediated pathway, has a role in GBM. We show that the alternative or non-canonical Notch pathway functioning through Deltex1 (DTX1) mediates key features of glioblastoma cell aggressiveness. For example, DTX1 activates the RTK/PI3K/PKB and the MAPK/ERK mitotic pathways and induces anti-apoptotic Mcl-1. The clonogenic and growth potential of established glioma cells correlated with DTX1 levels. Microarray gene expression analysis further identified a DTX1-specific, MAML1-independent transcriptional program - including - which is functionally linked to the changes in tumor cell aggressiveness. Over-expression of DTX1 increased cell migration and invasion correlating to ERK activation, miR-21 levels and endogenous Notch levels. In contrast to high and intermediate expressors, patients with low levels have a more favorable prognosis. The alternative Notch pathway via DTX1 appears to be an oncogenic factor in glioblastoma and these findings offer new potential therapeutic targets.
    PLoS ONE 02/2013; 8(2):e57793. DOI:10.1371/journal.pone.0057793 · 3.23 Impact Factor
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