Papers - NAKAJIMA, Kazunori

The secreted glycoprotein Reelin suppresses the proliferation and regulates the distribution of oligodendrocyte progenitor cells in the embryonic neocortex.

Himari Ogino, Tsuzumi Nakajima, Yuki Hirota, Kohki Toriuchi, Mineyoshi Aoyama, Kazunori Nakajima, and Mitsuharu Hattori.

J. Neurosci. 40 ( 40 ) 7625 - 7636 2020.09

Research paper (scientific journal), Joint Work, Accepted

Two-photon voltage imaging of spontaneous activity from multiple neurons reveals network activity in brain tissue.

Binglun Li, Mariya Chavarha, Yuho Kobayashi, Satoshi Yoshinaga, Kazunori Nakajima, Michael Z. Lin, and Takafumi Inoue

iScience 23 ( 8 ) 101363 2020.08

Research paper (scientific journal), Joint Work, Accepted

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Recording the electrical activity of multiple neurons simultaneously would greatly facilitate studies on the function of neuronal circuits. The combination of the fast scanning by random-access multiphoton microscopy (RAMP) and the latest two-photon-compatible high-performance fluorescent genetically encoded voltage indicators (GEVIs) has enabled action potential detection in deep layers in in vivo brain. However, neuron connectivity analysis on optically recorded action potentials from multiple neurons in brain tissue has yet to be achieved. With high expression of a two-photon-compatible GEVI, ASAP3, via in utero electroporation and RAMP, we achieved voltage recording of spontaneous activities from multiple neurons in brain slice. We provide evidence for the developmental changes in intralaminar horizontal connections in somatosensory cortex layer 2/3 with a greater sensitivity than calcium imaging. This method thus enables investigation of neuronal network connectivity at the cellular resolution in brain tissue.

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VLDLR is not essential for Reelin-induced neuronal aggregation but suppresses neuronal invasion into the marginal zone.（Selected to appear as a Research Highlight）

Hirota, Y. ,Nakajima,K.

Development 147 ( 12 ) 189936 2020.06

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

Neuron-derived VEGF contributes to cortical and hippocampal development independently of VEGFR1/2-mediated neurotrophism.

Keisuke Okabe, Hugh Fukada, Ikue Tai-Nagara, Tomofumi Ando, Takao Honda, Kazunori Nakajima, Norihiko Takeda, Guo-Hua Fong, Masatsugu Ema, and Yoshiaki Kubota

Dev. Biol. (Dev. Biol.)  459 ( 2 ) 65 - 71 2020.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00121606

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© 2019 The Authors Vascular endothelial growth factor (VEGF) is a potent mitogen critical for angiogenesis and organogenesis. Deletion or inhibition of VEGF during development not only profoundly suppresses vascular outgrowth, but significantly affects the development and function of various organs. In the brain, VEGF is thought to not only promote vascular growth, but also directly act on neurons as a neurotrophic factor by activating VEGF receptors. In the present study, we demonstrated that deletion of VEGF using hGfap-Cre line, which recombines genes specifically in cortical and hippocampal neurons, severely impaired brain organization and vascularization of these regions. The mutant mice had motor deficits, with lethality around the time of weaning. Multiple reporter lines indicated that VEGF was highly expressed in neurons, but that its cognate receptors, VEGFR1 and 2 were exclusive to endothelial cells in the brain. In accordance, mice lacking neuronal VEGFR1 and VEGFR2 did not exhibit neuronal deformities or lethality. Taken together, our data suggest that neuron-derived VEGF contributes to cortical and hippocampal development likely through angiogenesis independently of direct neurotrophic effects mediated by VEGFR1 and 2.

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Role of the immune system in the development of the central nervous system.

Keiko Morimoto and Kazunori Nakajima* (*corresponding author)

Front. Neurosci. (Frontiers in Neuroscience)  13 2019.09

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted,  ISSN  16624548

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© Copyright © 2019 Morimoto and Nakajima. The central nervous system (CNS) and the immune system are both intricate and highly organized systems that regulate the entire body, with both sharing certain common features in developmental mechanisms and operational modes. It is known that innate immunity-related molecules, such as cytokines, toll-like receptors, the complement family, and acquired immunity-related molecules, such as the major histocompatibility complex and antibody receptors, are also expressed in the brain and play important roles in brain development. Moreover, although the brain has previously been regarded as an immune-privileged site, it is known to contain lymphatic vessels. Not only microglia but also lymphocytes regulate cognition and play a vital role in the formation of neuronal circuits. This review provides an overview of the function of immune cells and immune molecules in the CNS, with particular emphasis on their effect on neural developmental processes.

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Both excitatory and inhibitory neurons transiently form clusters at the outermost region of the developing mammalian cerebral neocortex

Minkyung Shin, Ayako Kitazawa, Satoshi Yoshinaga, Kanehiro Hayashi, Yukio Hirata, Colette Dehay, Ken-ichiro Kubo*, and Kazunori Nakajima* (*corresponding authors)(M. Shin and A. Kitazawa are co-first authors)

J. Comp. Neurol. (Journal of Comparative Neurology)  527 ( 10 ) 1577 - 1597 2019.07

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted,  ISSN  00219967

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© 2019 Wiley Periodicals, Inc. During development of the mammalian cerebral neocortex, postmitotic excitatory neurons migrate toward the outermost region of the neocortex. We previously reported that this outermost region is composed of densely packed relatively immature neurons; we named this region, which is observed during the late stage of mouse neocortical development, the “primitive cortical zone (PCZ).” Here, we report that postmigratory immature neurons spend about 1–1.5 days in the PCZ. An electron microscopic analysis showed that the neurons in the PCZ tend to be in direct contact with each other, mostly in a radial direction, forming “primitive neuronal clusters” with a height of 3–7 cells and a width of 1–2 cells. A time-course analysis of fluorescently labeled neurons revealed that the neurons took their positions within the primitive clusters in an inside-out manner. The neurons initially participated in the superficial part of the clusters, gradually shifted their relative positions downward, and then left the clusters at the bottom of this structure. GABAergic inhibitory interneurons were also found within the primitive clusters in the developing mouse neocortex, suggesting that some clusters are composed of both excitatory neurons and inhibitory interneurons. Similar clusters were also observed in the outermost region of embryonic day (E) 78 cynomolgus monkey occipital cortex and 23 gestational week (GW) human neocortices. In the primate neocortices, including human, the presumptive primitive clusters seemed to expand in the radial direction more than that observed in mice, which might contribute to the functional integrity of the primate neocortex.

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Drebrin-like (Dbnl) controls neuronal migration via regulating N-cadherin expression in the developing cerebral cortex

Seika Inoue, Kanehiro Hayashi, Kyota Fujita, Kazuhiko Tagawa, Hitoshi Okazawa, Ken-ichiro Kubo, and Kazunori Nakajima* (*corresponding author)

J. Neurosci. (Journal of Neuroscience)  39 ( 4 ) 678 - 691 2019.01

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted,  ISSN  02706474

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© 2019 the authors. The actin cytoskeleton is crucial for neuronal migration in the mammalian developing cerebral cortex. The adaptor protein Drebrin-like (Dbnl) plays important roles in reorganization of the actin cytoskeleton, dendrite formation, and endocytosis by interacting with F-actin, cobl, and dynamin. Although Dbnl is known to be expressed in the brain, the functions of this molecule during brain development are largely unknown. In this study, to examine the roles of Dbnl in the developing cerebral cortex, we conducted experiments using mice of both sexes with knockdown of Dbnl, effected by in utero electroporation, in the migrating neurons of the embryonic cortex. Time-lapse imaging of the Dbnl-knockdown neurons revealed that the presence of Dbnl is a prerequisite for appropriate formation of processes in the multipolar neurons in the multipolar cell accumulation zone or the deep part of the subventricular zone, and for neuronal polarization and entry into the cortical plate. We found that Dbnl knockdown decreased the amount of N-cadherin protein expressed on the plasma membrane of the cortical neurons. The defect in neuronal migration caused by Dbnl knockdown was rescued by moderate overexpression of N-cadherin and αN-catenin or by transfection of the phospho-mimic form(Y337E, Y347E), but not the phospho-resistant form(Y337F, Y347F), of Dbnl. These results suggest that Dbnl controls neuronal migration, neuronal multipolar morphology, and cell polarity in the developing cerebral cortex via regulating N-cadherin expression.

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Subtype specification of cerebral cortical neurons in their immature stages.

Koji Oishi* and Kazunori Nakajima* (* are the corresponding authors)

Neurochem. Res. (Neurochemical Research)  43 ( 1 ) 238 - 244 2018.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  03643190

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© 2017, Springer Science+Business Media, LLC, part of Springer Nature. The diversification of neuronal subtypes during corticogenesis is fundamental to the establishment of the complex cortical structure. Although subtype specification has been assumed to occur in neural progenitor cells, increasing evidence has begun to reveal the plasticity of subtype determination in immature neurons. Here, we summarize recent findings regarding the regulation of subtype specification during later periods of neuronal differentiation, such as the post-mitotic and post-migratory stages. We also discuss thalamocortical axons as an extra-cortical cue that provides information on the subtype determination of immature cortical neurons.

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ApoER2 controls not only neuronal migration in the intermediate zone, but also termination of migration in the developing cerebral cortex. (Featured on the cover)

Yuki Hirota, Ken-ichiro Kubo, Takahiro Fujino, Tokuo T. Yamamoto, and Kazunori Nakajima* (* is the corresponding author)

Cereb. Cortex (Cerebral Cortex)  28 ( 1 ) 238 - 244 2018.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  10473211

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© The Author 2016. Published by Oxford University Press. All rights reserved. Neuronal migration contributes to the establishment of mammalian brain. The extracellular protein Reelin sends signals to various downstream molecules by binding to its receptors, the apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor and exerts essential roles in the neuronal migration and formation of the layered neocortex. However, the cellular and molecular functions of Reelin signaling in the cortical development are not yet fully understood. Here, to gain insight into the role of Reelin signaling during cortical development, we examined the migratory behavior of Apoer2-deficient neurons in the developing brain. Stage-specific labeling of newborn neurons revealed that the neurons ectopically invaded the marginal zone (MZ) and that neuronal migration of both early- and late-born neurons was disrupted in the intermediate zone (IZ) in the Apoer2 KO mice. Rescue experiments showed that ApoER2 functions both in cell-autonomous and noncell-autonomous manners, that Rap1, integrin, and Akt are involved in the termination of migration beneath the MZ, and that Akt also controls neuronal migration in the IZ downstream of ApoER2. These data indicate that ApoER2 controls multiple processes in neuronal migration, including the early stage of radial migration and termination of migration beneath the MZ in the developing neocortex.

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Enhanced expression of Pafah1b1 causes over-migration of cerebral cortical neurons into the marginal zone.

Kei-ichi Katayama, Kanehiro Hayashi, Seika Inoue, Kazushige Sakaguchi, and Kazunori Nakajima* (* is the corresponding author)

Brain Struct. Funct. 222 ( 9 ) 4283 - 4291 2017.12

Research paper (scientific journal), Joint Work, Accepted

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CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations.

Hironobu Okuno，Francois Renault Mihara, Shigeki Ohta, Kimiko Fukuda, Kenji Kurosawa, Wado Akamatsu, Tsukasa Sanosaka, Jun Kohyama, Kanehiro Hayashi, Kazunori Nakajima, Takao Takahashi, Joanna Wysocka, Kenjiro Kosaki, and Hideyuki Okano

eLife 6 ( e21114 )  2017.11

Research paper (scientific journal), Joint Work, Accepted

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Dendritic homeostasis disruption in a novel frontotemporal dementia mouse model expressing cytoplasmic fused in sarcoma.

Gen Shiihashi, Daisuke Ito, Itaru Arai, Yuki Kobayashi, Kanehiro Hayashi, Shintaro Otsuka, Kazunori Nakajima, Michisuke Yuzaki, Shigeyoshi Itohara, and Norihiro Suzuki

EBioMedicine 24   102 - 115 2017.10

Research paper (scientific journal), Joint Work, Accepted

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Impaired dendritic growth and positioning of cortical pyramidal neurons by activation of aryl hydrocarbon receptor signaling in the developing mouse.

Eiki Kimura, Ken-ichiro Kubo, Toshihiro Endo, Wenting Ling, Kazunori Nakajima, Masaki Kakeyama, and Chiharu Tohyama

PLoS One 12 ( 8 ) e0183497 2017.08

Research paper (scientific journal), Joint Work, Accepted

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Association of impaired neuronal migration with cognitive deficits in extremely preterm infants

Ken-ichiro Kubo*, Kimiko Deguchi, Taku Nagai, Yukiko Ito, Keitaro Yoshida, Toshihiro Endo, Seico Benner, Wei Shan, Ayako Kitazawa, Michihiko Aramaki, Kazuhiro Ishii, Minkyung Shin, Yuki Matsunaga, Kanehiro Hayashi, Masaki Kakeyama, Chiharu Tohyama, Kenji F. Tanaka, Kohichi Tanaka, Sachio Takashima, Masahiro Nakayama, Masayuki Itoh, Yukio Hirata, Barbara Antalffy, Dawna D. Armstrong, Kiyofumi Yamada, Ken Inoue*, and Kazunori Nakajima* (* are the co-corresponding authors)(K. Kubo and K. Deguchi are co-first authors)

JCI Insight, 2 ( 10,e88609 )  2017.05

Research paper (scientific journal), Joint Work, Accepted

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A crossroad of neuronal diversity to build circuitry.

Satoshi Yoshinaga and Kazunori Nakajima* (*corresponding author)

Science 356 ( 6336 ) 376 - 377 2017.04

Research paper (scientific journal), Joint Work

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Control of neuronal migration and aggregation by Reelin signaling in the developing cerebral cortex.

Yuki Hirota and Kazunori Nakajima* (* is the corresponding author)

Front. Cell Dev. Biol. 5 ( 40 )  2017.04

Research paper (scientific journal), Joint Work, Accepted

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Reelin transiently promotes N-cadherin-dependent neuronal adhesion during mouse cortical development.

Yuki Matsunaga, Mariko Noda, Hideki Murakawa, Kanehiro Hayashi, Arata Nagasaka, Seika Inoue, Takaki Miyata, Takashi Miura, Ken-ichiro Kubo, and Kazunori Nakajima* (* is the corresponding author)(Y. Matsunaga and M. Noda are co-first authors)

Proc. Natl. Acad. Sci. U.S.A. 114 ( 8 ) 2048 - 2053 2017.02

Research paper (scientific journal), Joint Work, Accepted

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Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse.

Eiki Kimura, Ken-ichiro Kubo, Toshihiro Endo, Kazunori Nakajima, Masaki Kakeyama, and Chiharu Tohyama

J. Toxicol. Sci. 42 ( 1 ) 25 - 30 2017.02

Research paper (scientific journal), Joint Work, Accepted

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DISC1 a key molecular lead in psychiatry and neurodevelopment: No-More Disrupted-in-Schizophrenia.

Minae Niwa, Tyler Cash-Padgett, Ken-Ichiro Kubo, Atsushi Saito, Kazuhiro Ishii, Akiko Sumitomo, Yu Taniguchi, Koko Ishizuka, Hanna Jaaro-Peled, Toshifumi Tomoda, Kazunori Nakajima, Akira Sawa, and Atsushi Kamiya

Mol. Psychiatry 21 ( 11 ) 1488 - 1489 2016.11

Research paper (scientific journal), Accepted

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Reelin and neuropsychiatric disorders.

Kazuhiro Ishii, Ken-ichiro Kubo, and Kazunori Nakajima* (* is the corresponding author)

Front. Cell. Neurosci. 10 ( 229 )  2016.10

Research paper (scientific journal), Joint Work, Accepted

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