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 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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amyloid Precursor Protein Secretases
-
Animals
-
Aspartic Acid Endopeptidases / metabolism
-
Cell Differentiation / physiology
-
Cell Line
-
Cell Membrane / metabolism
-
Cerebellar Cortex / cytology
-
DNA-Binding Proteins / physiology
-
Endopeptidases
-
Humans
-
Ligands
-
Mice
-
Mice, Knockout
-
Nerve Tissue Proteins / deficiency
-
Nerve Tissue Proteins / genetics
-
Nerve Tissue Proteins / metabolism*
-
Nerve Tissue Proteins / physiology
-
Neuroglia / cytology*
-
Neuroglia / metabolism*
-
Neuroglia / pathology
-
Neuroglia / physiology
-
Neurons / metabolism*
-
Protein Structure, Tertiary / physiology
-
Purkinje Cells / metabolism*
-
Receptor, Notch1
-
Receptors, Cell Surface / deficiency
-
Receptors, Cell Surface / genetics
-
Receptors, Cell Surface / metabolism*
-
Receptors, Cell Surface / physiology
-
Signal Transduction / physiology
-
Transcription Factors / metabolism*
-
Transcriptional Activation / physiology
-
Ubiquitin-Protein Ligases
Substances
-
DNA-Binding Proteins
-
Dner protein, mouse
-
Ligands
-
NOTCH1 protein, human
-
Nerve Tissue Proteins
-
Notch1 protein, mouse
-
Receptor, Notch1
-
Receptors, Cell Surface
-
Transcription Factors
-
Dtx1 protein, mouse
-
Ubiquitin-Protein Ligases
-
Amyloid Precursor Protein Secretases
-
Endopeptidases
-
Aspartic Acid Endopeptidases
-
BACE1 protein, human
-
Bace1 protein, mouse