Reelin-Nrp1 Interaction Regulates Neocortical Dendrite Development in a Context-Specific Manner
Year: 2020
Type: article
Abstract: Reelin plays versatile roles in neocortical development. The C-terminal region (CTR) of Reelin is required for the correct formation of the superficial structure of the neocortex; however, the mechanisms by which this position-specific effect occurs remain largely unknown. In this study, we demonstrate that Reelin with an intact CTR binds to neuropilin-1 (Nrp1), a transmembrane protein. Both male and female mice were used. Nrp1 is localized with very-low-density lipoprotein receptor (VLDLR), a canonical Reelin receptor, in the superficial layers of the developing neocortex. It forms a complex with VLDLR, and this interaction is modulated by the alternative splicing of VLDLR. Reelin with an intact CTR binds more strongly to the VLDLR/Nrp1 complex than to VLDLR alone. Knockdown of Nrp1 in neurons leads to the accumulation of Dab1 protein. Since the degradation of Dab1 is induced by Reelin signaling, it is suggested that Nrp1 augments Reelin signaling. The interaction between Reelin and Nrp1 is required for normal dendritic development in superficial-layer neurons. All of these characteristics of Reelin are abrogated by proteolytic processing of the six C-terminal amino acid residues of Reelin (0.17% of the whole protein). Therefore, Nrp1 is a coreceptor molecule for Reelin and, together with the proteolytic processing of Reelin, can account for context-specific Reelin function in brain development. SIGNIFICANCE STATEMENTReelin often exhibits a context-dependent function during brain development; however, its underlying mechanism is not well understood. We found that neuropilin-1 (Nrp1) specifically binds to the CTR of Reelin and acts as a coreceptor for very-low-density lipoprotein receptor (VLDLR). The Nrp1/VLDLR complex is localized in the superficial layers of the neocortex, and its interaction with Reelin is essential for proper dendritic development in superficial-layer neurons. This study provides the first mechanistic evidence of the context-specific function of Reelin (>3400 residues) regulated by the C-terminal residues and Nrp1, a component of the canonical Reelin receptor complex.
Source: Journal of Neuroscience
Authors: Takao Kohno, Keisuke Ishii, Yuki Hirota, Takao Honda, Makoto Makino, Takahiko Kawasaki, Kazunori Nakajima, Mitsuharu Hattori
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Awards: The regulatory mechanism of Reelin and its importance in neuropsychiatric disorders, G2198244473, 海馬層構造の形成と維持に関わる新規メカニズムの解明と、その疾患治療への応用, Molecular mechanisms regulating the formation of collateral branches, Basic and applied research on the secreted protein, Reelin, oriented toward the understanding and treatment of psychiatric disorders., The role of a secreted protein Reelin in the brain and its therapeutic application., Mechanisms of cortical formation mediated by neuronal repulsive signals, Control of neuronal morphology by using a specific fatty acid, G4979813573, Study of neocortical layer1 maintenance mechanism through Reelin-Dab1 signaling pathway, Mechanisms of corticogenesis in the developing brain, Mechanisms and significance of spatiotemporal specific Reelin function in the cerebral cortex, G877361773
OpenAlex ID: W3091003608