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

Abstract

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 γ-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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Figure 1: Interaction of DNER with Notch1 via the extracellular domain.
Figure 2: DNER transactivates CSL-dependent Notch signaling pathway in C2C12 cells.
Figure 3: DNER specifically binds to Notch1-expressing Bergmann glia.
Figure 4: DNER promotes the process formation of Bergmann glia via a Deltex-dependent Notch signaling pathway in vitro.
Figure 5: Deltex-dependent Notch signaling regulates the process formation of Bergmann glia.
Figure 6: Decrease in Bergmann glial fibers in DNER-deficient mice.
Figure 7: DNER deficiency causes abnormal Bergmann glial development.

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Acknowledgements

We thank H. Takeshima for Dner−/− mice, and T. Honjo, K. Kuroda, M. Watanabe, A. Tokunaga, H. Okano, S. Nakagawa and H. Okado for reagents and invaluable advice. We also thank R. Kageyama, C. Tabin, T. Uemura, Y. Shima and R.T. Yu for critical reading of the manuscript. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan to M.K. and a Fellowship from the Japan Society for the Promotion of Science for Junior Scientists to M.E.

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Correspondence to Mineko Kengaku.

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Supplementary information

Supplementary Fig. 1

CSL-dependent Notch signaling pathway in C2C12 cells. (PDF 184 kb)

Supplementary Fig. 2

Expression of canonical Notch ligands are unaltered by DNER deficiency. (PDF 1049 kb)

Supplementary Fig. 3

DNER deficiency affects neither the morphology of Purkinje cells nor the proliferation of Bergmann glia. (PDF 1096 kb)

Supplementary Fig. 4

Granule cell migration is retarded in DNER-deficient mice. (PDF 974 kb)

Supplementary Fig. 5

Proposed model of DNER-Notch signaling during Bergmann glial development. (PDF 2513 kb)

Supplementary Methods (PDF 51 kb)

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Eiraku, M., Tohgo, A., Ono, K. et al. DNER acts as a neuron-specific Notch ligand during Bergmann glial development. Nat Neurosci 8, 873–880 (2005). https://doi.org/10.1038/nn1492

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