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Reelin-DBNL signaling regulates neuronal migration via N-cadherin/α-N-catenin complex in the intermediate zone and multipolar cell accumulate zone of the developing mouse cerebral neocortex
発生期マウス大脳新皮質深部 において、リーリン- DBNLシグナルはNカドヘリン/α-N-カテニンを介して神経細胞移動を制御する
Inoue Seika（井上 聖香）1，林 周宏1，藤田 慶大2，田川 一彦2，岡澤 均2，久保 健一郎1，仲嶋 一範1
1Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
2Department of Neuropathology, Medical Research Institute, Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan
Reelin has a critical role for the development of the mammalian cerebral neocortex, because the Reelin-deficient mouse shows roughly inverted layers in the cerebral neocortex. Reelin is mainly expressed in the marginal zone (MZ), but a small amount of the protein also exists in the multipolar cell accumulation zone (MAZ). There are a couple of Reelin receptors, low-density lipoprotein receptor-related protein 8 (LRP8/ApoER2) and very low-density lipoprotein receptor (VLDLR). ApoER2 is mainly produced in the neurons located in the lower intermediate zone (IZ) and MAZ, whereas VLDLR is localized on the leading processes of migrating neurons in the MZ of the developing cerebral neocortex (Hirota et al., 2015). Although deficiency of either Apoer2 or Vldlr causes defect in the layer formation in the mouse cerebral neocortex, the Apoer2 mutant mouse exhibits more serious phenotypes than the Vldlr mutant mice. These evidences suggest the action of Reelin in the lower IZ and MAZ is critical for the layer formation in the mammalian cerebral neocortex. In the present study, we identified Drebrin-like (DBNL) as a novel protein phosphorylated by Reelin in the lower part of the developing cerebral neocortex by a phospho-proteomics analysis. Short-hairpin RNA (shRNA)-mediated knockdown of DBNL in neocortical progenitors using in utero electroporation showed the deficit of neuronal migration, process formation and polarization during multipolar migration and multipolar-bipolar transition through the regulation of α-N-catenin and N-cadherin. Our results reveal that Reelin-DBNL-N-cadherin/α-N-catenin pathway is pivotal for neuronal migration in the lower IZ and MAZ. | | WD10-2
Structural view of radial glial cells in the developing mouse neocortex
発生中のマウス大脳新皮質における放射状グリア細胞の構造的な特徴について
Shin Minkyung，北澤 彩子，吉永 怜史，林 周宏，久保 健一郎，仲嶋 一範
The Department of Anatomy, Keio University
In the developing mammalian neocortex, newly born neurons migrate along radial glial fibers toward the outermost surface of the brain. Radial fibers are extended from radial glial cells (RG cells) and provide the scaffold for migrating neurons that finally form an organized cortical plate (CP) in a birth-date dependent ‘inside-out’ manner. Recently, we have found that the radial fibers are individually separated in the CP. On the other hand, in Reelin-deficient mouse, reeler, some radial fibers are arranged as bundles in the CP, which raises the possibility that Reelin could affect the dissociation of fibers in the CP, directly or indirectly. Since the CP layers are disorganized in reeler, detachment between radial fibers might be necessary for guiding neurons up to the final destination. Furthermore, our time-lapse analysis showed that radial fibers themselves could actively interact with neighboring fibers by using small tangential protrusions. Based on these observations, we hypothesized that the RG cells could communicate with the surrounding environment, including neighboring radial fibers, to regulate their capacities. |
