Details of the Researcher

PHOTO

Takako Kikkawa
Section
Graduate School of Medicine
Job title
Senior Assistant Professor
Degree

  • 博士（医学）（東北大学）

  • 修士（医科学）（東北大学）

e-Rad No.
90727851
Profile

2008年 埼玉大学理学部卒。 2013年 東北大学大学院医学系研究科修了（医学博士）。

2012年から日本学術振興会特別研究員（DC2）に採用され、学位短期取得により、2013年から日本学術振興会特別研究員（PD）へと移行。

2014年から東北大学大学院医学系研究科助教、2021年から同所属 プロミネントリサーチフェロー（助教）を経て、2024年より同所属 講師（現職）。

専門分野：神経発生学、神経発達症、神経変性疾患、脂質生物学、栄養学、エピジェネティクス

モデル生物：マウス

現在の主要なテーマ：
＊脳の発生発達維持の分子機構
＊神経発達症を引き起こす遺伝子・環境因子・エピジェネティック要因の解明
＊神経変性疾患におけるバイオマーカー研究
＊脂質バランスならびに脂質過酸化にともなう細胞死（フェロトーシス）解析

Research History 6

  • 2024/04 - Present
    Tohoku University　Graduate School of Medicine

  • 2021/07 - 2024/03
    Tohoku University　Graduate School of Medicine

  • 2014/04 - 2021/06
    Tohoku University　Graduate School of Medicine

  • 2013/10 - 2014/03
    日本学術振興会 特別研究員 PD

  • 2012/04 - 2013/09
    日本学術振興会 特別研究員 DC2

  • 2010/04 - 2012/03
    東北大学グローバルCOE「脳神経科学を社会へ還流する教育研究拠点」Research Assistant

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Education 3

  • Tohoku University　Graduate School of Medicine

    2010/04 - 2013/09

  • Tohoku University　Graduate School of Medicine

    2008/04 - 2010/03

  • Saitama University　Faculty of Science　Department of Regulation-Biology

    2004/04 - 2008/03

Professional Memberships 5

  • 日本神経化学会

  • 日本神経精神薬理学会

  • THE JAPANESE ASSOCIATION OF ANATOMISTS

  • THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

  • THE JAPAN NEUROSCIENCE SOCIETY

Research Areas 5

  • Life sciences / Anatomy /

  • Life sciences / Developmental biology /

  • Life sciences / Neuroscience - general /

  • Life sciences / Neuropathology /

  • Life sciences / Nutrition and health science /

Awards 12

  1. 公益財団法人 艮陵医学振興会「勾坂記念賞」

    2022

  2. 日本神経精神薬理学会「JSNP Excellent Presentation Award for CINP 2023」

    2022

  3. 24th Biennial Meeting of the International Society for Developmental Neuroscience「Best Poster award」

    2022

  4. 日本解剖学会 第67回東北・北海道連合支部学術集会「学会賞」

    2021

  5. 東北大学 優秀女性研究者賞「紫千代萩賞」

    2019

  6. 第13回 成体脳のニューロン新生懇談会「優秀演題賞」

    2017

  7. International Federation of University Women「Hegg Hoffet賞」

    2013

  8. 大学女性協会「国内奨学生」

    2013

  9. 東北大学大学院医学系研究科 第４回リトリート大学院生研究発表会「Young Investigator’s Question Award」

    2013

  10. 東北大学グローバルCOE 脳神経科学を社会へ還流する教育研究拠点「支倉フェローシップ」

    2011

  11. 東北大学グローバルCOE 脳神経科学を社会へ還流する教育研究拠点「支倉フェローシップ」

    2010

  12. 菅原医学振興基金 奨学生

    2010

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Papers 36

  1. Sex-Difference in Olfactory Interhemispheric Malformation Caused by Pax6 Haploinsufficiency

    Natsumi Joko, Takako Kikkawa*, Takayoshi Inoue, Noriko Osumi* (*corresponding author)

    The Tohoku Journal of Experimental Medicine　2025/06/05

    Publisher: Tohoku University Medical Press

    DOI： 10.1620/tjem.2025.j068 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  2. A Transcriptomic Dataset of Embryonic Murine Telencephalon of Fmr1-Deficient Mice Peer-reviewed

    Sara Ebrahimiazar, Takako Kikkawa*, Yohei Minakuchi, Satoshi Miyashita, Shyu Manabe, Mikio Hoshino, Atsushi Toyoda, Noriko Osumi* (*corresponding author)

    Scientific Data　12　(1)　2025/06/02

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41597-025-05104-7 　

    eISSN： 2052-4463

  3. In preprints: unraveling a new non-canonical role of Cyclin D1 in corticogenesis Peer-reviewed

    Noriko Osumi, Takako Kikkawa

    Development　152　(9)　2025/04/29

    Publisher: The Company of Biologists

    DOI： 10.1242/dev.204829 　

    ISSN： 0950-1991

    eISSN： 1477-9129

  4. Sex-specific effects of prenatal bisphenol A exposure on transcriptome-interactome profiles of autism candidate genes in neural stem cells from offspring hippocampus Peer-reviewed

    Kasidit Kasitipradit, Surangrat Thongkorn, Songphon Kanlayaprasit, Thanit Saeliw, Pattanachat Lertpeerapan, Pawinee Panjabud, Depicha Jindatip, Valerie W. Hu, Takako Kikkawa, Noriko Osumi, Tewarit Sarachana

    Scientific Reports　15　(1)　2025/01/22

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41598-025-86392-2 　

    eISSN： 2045-2322

  5. Kinesin-like motor protein KIF23 maintains neural stem and progenitor cell pools in the developing cortex Peer-reviewed

    Sharmin Naher, Kenji Iemura, Satoshi Miyashita, Mikio Hoshino, Kozo Tanaka, Shinsuke Niwa, Jin-Wu Tsai, Takako Kikkawa*, Noriko Osumi* (*corresponding author)

    The EMBO Journal　2024/12/04

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s44318-024-00327-7 　

    eISSN： 1460-2075

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    Abstract Accurate mitotic division of neural stem and progenitor cells (NSPCs) is crucial for the coordinated generation of progenitors and mature neurons, which determines cortical size and structure. While mutations in the kinesin-like motor protein KIF23 gene have been recently linked to microcephaly in humans, the underlying mechanisms remain elusive. Here, we explore the pivotal role of KIF23 in embryonic cortical development. We characterize the dynamic expression of KIF23 in the cortical NSPCs of mice, ferrets, and humans during embryonic neurogenesis. Knockdown of Kif23 in mice results in precocious neurogenesis and neuronal apoptosis, attributed to an accelerated cell cycle exit, likely resulting from disrupted mitotic spindle orientation and impaired cytokinesis. Additionally, KIF23 depletion perturbs the apical surface structure of NSPCs by affecting the localization of apical junction proteins. We further demonstrate that the phenotypes induced by Kif23 knockdown are rescued by introducing wild-type human KIF23, but not by a microcephaly-associated variant. Our findings unveil a previously unexplored role of KIF23 in neural stem and progenitor cell maintenance via regulating spindle orientation and apical structure in addition to cytokinesis, shedding light on microcephaly pathogenesis.

  6. Vitamin E supplementation prevents ferroptosis in round spermatids of aged mice

    Jasper Germeraad, Takako Kikkawa, Noriko Osumi

    2024/10/24

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1101/2024.10.21.619554 　

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    Abstract Germ cell depletion in the aged testes has traditionally been attributed to removal by apoptosis. This study aimed to determine whether ferroptosis, an alternative form of cell death driven by iron-dependent lipid peroxidation, also contributes to germ cell loss in the lipid-rich environment of the testis. Here, we demonstrate that pre-meiotic cells are eliminated via apoptosis, whereas post-meiotic round spermatids (RSs) are mainly removed through ferroptosis. Surprisingly, we detected a greater abundance of Y-chromosome-bearing RSs (Y-RSs) than X-carrying RSs (X-RSs) in the aged testis, implying that X-RSs might be more prone to ferroptosis. Young mice fed a vitamin E (VE) deficient diet recapitulated age-related phenotypes, while VE supplementation prevented ferroptosis and promoted the survival of X-RSs in aged mice. Overall, this study reveals that aging causes ferroptosis in RSs, specifically impacting X-RSs, which can be prevented by VE supplementation, effectively reversing age-induced deterioration and contributing to healthy testicular aging.

  7. A Transcriptomic Dataset of Embryonic Murine Telencephalon Peer-reviewed

    Shohei Ochi, Shyu Manabe, Takako Kikkawa, Sara Ebrahimiazar, Ryuichi Kimura, Kaichi Yoshizaki, Noriko Osumi

    Scientific Data　11　(1)　2024/06/05

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41597-024-03421-x 　

    eISSN： 2052-4463

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    Abstract Sex bias is known in the prevalence/pathology of neurodevelopmental disorders. Sex-dependent differences of the certain brain areas are known to emerge perinatally through the exposure to sex hormones, while gene expression patterns in the rodent embryonic brain does not seem to be completely the same between male and female. To investigate potential sex differences in gene expression and cortical organization during the embryonic period in mice, we conducted a comprehensive analysis of gene expression for the telencephalon at embryonic day (E) 11.5 (a peak of neural stem cell expansion) and E14.5 (a peak of neurogenesis) using bulk RNA-seq data. As a result, our data showed the existence of notable sex differences in gene expression patterns not obviously at E11.5, but clearly at E14.5 when neurogenesis has become its peak. These data can be useful for exploring potential contribution of genes exhibiting sex differences to the divergence in brain development. Additionally, our data underscore the significance of studying the embryonic period to gain a deeper understanding of sex differences in brain development.

  8. Investigating the impact of paternal aging on murine sperm miRNA profiles and their potential link to autism spectrum disorder Peer-reviewed

    Kazusa Miyahara, Misako Tatehana, Takako Kikkawa, Noriko Osumi

    Scientific Reports　13　(1)　2023/12/07

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41598-023-47878-z 　

    eISSN： 2045-2322

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    Abstract Paternal aging has consistently been linked to an increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), in offspring. Recent evidence has highlighted the involvement of epigenetic factors. In this study, we aimed to investigate age-related alterations in microRNA (miRNA) profiles of mouse sperm and analyze target genes regulated by differentially expressed miRNAs (DEmiRNAs). Microarray analyses were conducted on sperm samples from mice at different ages: 3 months (3 M), over 12 M, and beyond 20 M. We identified 26 miRNAs with differential expression between the 3 and 20 M mice, 34 miRNAs between the 12 and 20 M mice, and 2 miRNAs between the 3 and 12 M mice. The target genes regulated by these miRNAs were significantly associated with apoptosis/ferroptosis pathways and the nervous system. We revealed alterations in sperm miRNA profiles due to aging and suggest that the target genes regulated by these DEmiRNAs are associated with apoptosis and the nervous system, implying a potential link between paternal aging and an increased risk of neurodevelopmental disorders such as ASD. The observed age-related changes in sperm miRNA profiles have the potential to impact sperm quality and subsequently affect offspring development.

  9. 神経発達障害の原因となるRNA結合タンパク質の機能解明

    吉川 貴子, 大隅 典子

    東北医学雑誌　135　(2)　76-76　2023/12

    Publisher: 東北医学会

    ISSN： 0040-8700

  10. Regulation of mRNA Localization and Translation in Brain Development Invited

    Takako Kikkawa*, Sharmin Naher, Noriko Osumi* (*corresponding author)

    Neocortical Neurogenesis in Development and Evolution　649-663　2023/08/08

    Publisher: Wiley

    DOI： 10.1002/9781119860914.ch29 　

  11. 最先端医療の今 神経幹細胞内mRNA輸送による脳発生の制御

    吉川 貴子, 大隅 典子

    Medical Science Digest　49　(9)　496-498　2023/08

    Publisher: (株)ニュー・サイエンス社

    ISSN： 1347-4340

  12. 加齢に伴う性染色体比の変化はPax6に依存する(The age-associated sex chromosome ratio is altered in a Pax6 dependent manner)

    Jasper Germeraad, 吉川 貴子, 大隅 典子

    DOHaD研究　11　(3)　43-43　2023/08

    Publisher: (一社)日本DOHaD学会

    ISSN： 2187-2562

    eISSN： 2187-2597

  13. Deficiency of CHAMP1, a gene related to intellectual disability, causes impaired neuronal development and a mild behavioral phenotype International-journal Peer-reviewed

    Masayoshi Nagai, Kenji Iemura, Takako Kikkawa, Sharmin Naher, Satoko Hattori, Hideo Hagihara, Koh ichi Nagata, Hayato Anzawa, Risa Kugisaki, Hideki Wanibuchi, Takaya Abe, Kenichi Inoue, Kengo Kinoshita, Tsuyoshi Miyakawa, Noriko Osumi, Kozo Tanaka

    Brain Communications　4　(5)　fcac220　2022/08/30

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/braincomms/fcac220 　

    eISSN： 2632-1297

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    Abstract CHAMP1 is a gene associated with intellectual disability, which was originally identified as being involved in the maintenance of kinetochore–microtubule attachment. To explore the neuronal defects caused by CHAMP1 deficiency, we established mice that lack CHAMP1. Mice that are homozygous knockout for CHAMP1 were slightly smaller than wild type mice and died soon after birth on pure C57BL/6J background. Although gross anatomical defects were not found in CHAMP1-/- mouse brains, mitotic cells were increased in the cerebral cortex. Neuronal differentiation was delayed in CHAMP1-/- neural stem cells in vitro, which was also suggested in vivo by CHAMP1 knockdown. In a behavioral test battery, adult CHAMP1 heterozygous-knockout mice showed mild memory defects, altered social interaction, and depression-like behaviors. In transcriptomic analysis, genes related to neurotransmitter transport and neurodevelopmental disorder were downregulated in embryonic CHAMP1-/- brains. These results suggest that CHAMP1 plays a role in neuronal development, and CHAMP1-deficient mice resemble some aspects of individuals with CHAMP1 mutations.

  14. Regulation of male germline transmission patterns by the Trp53-Cdkn1a pathway International-journal Peer-reviewed

    Mito Kanatsu-Shinohara, Honda Naoki, Takashi Tanaka, Misako Tatehana, Takako Kikkawa, Noriko Osumi, Takashi Shinohara

    Stem Cell Reports　17　(9)　1924-1941　2022/08

    Publisher: Elsevier BV

    DOI： 10.1016/j.stemcr.2022.07.007 　

    ISSN： 2213-6711

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    A small number of offspring are born from the numerous sperm generated from spermatogonial stem cells (SSCs). However, little is known regarding the rules and molecular mechanisms that govern germline transmission patterns. Here we report that the Trp53 tumor suppressor gene limits germline genetic diversity via Cdkn1a. Trp53-deficient SSCs outcompeted wild-type (WT) SSCs and produced significantly more progeny after co-transplantation into infertile mice. Lentivirus-mediated transgenerational lineage analysis showed that offspring bearing the same virus integration were repeatedly born in a non-random pattern from WT SSCs. However, SSCs lacking Trp53 or Cdkn1a sired transgenic offspring in random patterns with increased genetic diversity. Apoptosis of KIT+ differentiating germ cells was reduced in Trp53- or Cdkn1a-deficient mice. Reduced CDKN1A expression in Trp53-deficient spermatogonia suggested that Cdkn1a limits genetic diversity by supporting apoptosis of syncytial spermatogonial clones. Therefore, the TRP53-CDKN1A pathway regulates tumorigenesis and the germline transmission pattern.

  15. The subcommissural organ maintains features of neuroepithelial cells in the adult mouse International-journal Peer-reviewed

    Laarni Grace Corales, Hitoshi Inada, Kotaro Hiraoka, Shun Araki, Shinya Yamanaka, Takako Kikkawa, Noriko Osumi

    Journal of Anatomy　241　(3)　820-830　2022/05/31

    Publisher: Wiley

    DOI： 10.1111/joa.13709 　

    ISSN： 0021-8782

    eISSN： 1469-7580

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    The subcommissural organ (SCO) is a part of the circumventricular organs located in the dorsocaudal region of the third ventricle at the entrance of the aqueduct of Sylvius. The SCO comprises epithelial cells and produces high molecular weight glycoproteins, which are secreted into the third ventricle and become part of Reissner's fibre in the cerebrospinal fluid. Abnormal development of the SCO has been linked with congenital hydrocephalus, a condition characterized by excessive accumulation of cerebrospinal fluid in the brain. In the present study, we characterized the SCO cells in the adult mouse brain to gain insights into the possible role of this brain region. Immunohistochemical analyses revealed that expression of Pax6, a transcription factor essential for SCO differentiation during embryogenesis, is maintained in the SCO at postnatal stages from P0 to P84. SCO cells in the adult brain expressed known neural stem/progenitor cell (NSPC) markers, Sox2 and vimentin. The adult SCO cells also expressed proliferating marker PCNA, although expression of another proliferation marker Ki67, indicating a G2 /M phase, was not detected. The SCO cells did not incorporate BrdU, a marker for DNA synthesis in the S phase. Therefore, the SCO cells have a potential for proliferation but are quiescent for cell division in the adult. The SCO cells also expressed GFAP, a marker for astrocytes or NSPCs, but not NeuN (for neurons). A few cells positive for Iba1 (microglia), Olig2 (for oligodendrocytes) and PDGFRα (oligodendrocyte progenitors) existed within or on the periphery of the SCO. These findings revealed that the SCO cells have a unique feature as secretory yet immature neuroepithelial cells in the adult mouse brain.

  16. Thirty Years’ History since the Discovery of Pax6: From Central Nervous System Development to Neurodevelopmental Disorders International-journal Peer-reviewed

    Shohei Ochi, Shyu Manabe, Takako Kikkawa, Noriko Osumi

    International Journal of Molecular Sciences　23　(11)　6115-6115　2022/05/30

    Publisher: MDPI AG

    DOI： 10.3390/ijms23116115 　

    eISSN： 1422-0067

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    Pax6 is a sequence-specific DNA binding transcription factor that positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system (CNS). As indicated by the morphological and functional abnormalities in spontaneous Pax6 mutant rodents, Pax6 plays pivotal roles in various biological processes in the CNS. At the initial stage of CNS development, Pax6 is responsible for brain patterning along the anteroposterior and dorsoventral axes of the telencephalon. Regarding the anteroposterior axis, Pax6 is expressed inversely to Emx2 and Coup-TF1, and Pax6 mutant mice exhibit a rostral shift, resulting in an alteration of the size of certain cortical areas. Pax6 and its downstream genes play important roles in balancing the proliferation and differentiation of neural stem cells. The Pax6 gene was originally identified in mice and humans 30 years ago via genetic analyses of the eye phenotypes. The human PAX6 gene was discovered in patients who suffer from WAGR syndrome (i.e., Wilms tumor, aniridia, genital ridge defects, mental retardation). Mutations of the human PAX6 gene have also been reported to be associated with autism spectrum disorder (ASD) and intellectual disability. Rodents that lack the Pax6 gene exhibit diverse neural phenotypes, which might lead to a better understanding of human pathology and neurodevelopmental disorders. This review describes the expression and function of Pax6 during brain development, and their implications for neuropathology.

  17. Multiple Functions of the Dmrt Genes in the Development of the Central Nervous System International-journal Peer-reviewed

    Takako Kikkawa*, Noriko Osumi (*corresponding author)

    Frontiers in Neuroscience　15　789583-789583　2021/12/09

    Publisher: Frontiers Media SA

    DOI： 10.3389/fnins.2021.789583 　

    eISSN： 1662-453X

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    The <italic>Dmrt</italic> genes encode the transcription factor containing the DM (doublesex and mab-3) domain, an intertwined zinc finger-like DNA binding module. While <italic>Dmrt</italic> genes are mainly involved in the sexual development of various species, recent studies have revealed that <italic>Dmrt</italic> genes, which belong to <italic>the DmrtA</italic> subfamily, are differentially expressed in the embryonic brain and spinal cord and are essential for the development of the central nervous system. Herein, we summarize recent studies that reveal the multiple functions of the <italic>Dmrt</italic> genes in various aspects of vertebrate neural development, including brain patterning, neurogenesis, and the specification of neurons.

  18. Autism-Related Transcription Factors Underlying the Sex-Specific Effects of Prenatal Bisphenol A Exposure on Transcriptome-Interactome Profiles in the Offspring Prefrontal Cortex International-journal Peer-reviewed

    Songphon Kanlayaprasit, Surangrat Thongkorn, Pawinee Panjabud, Depicha Jindatip, Valerie W. Hu, Takako Kikkawa, Noriko Osumi, Tewarit Sarachana

    International Journal of Molecular Sciences　22　(24)　13201-13201　2021/12/08

    Publisher: MDPI AG

    DOI： 10.3390/ijms222413201 　

    eISSN： 1422-0067

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    Bisphenol A (BPA) is an environmental risk factor for autism spectrum disorder (ASD). BPA exposure dysregulates ASD-related genes in the hippocampus and neurological functions of offspring. However, whether prenatal BPA exposure has an impact on genes in the prefrontal cortex, another brain region highly implicated in ASD, and through what mechanisms have not been investigated. Here, we demonstrated that prenatal BPA exposure disrupts the transcriptome–interactome profiles of the prefrontal cortex of neonatal rats. Interestingly, the list of BPA-responsive genes was significantly enriched with known ASD candidate genes, as well as genes that were dysregulated in the postmortem brain tissues of ASD cases from multiple independent studies. Moreover, several differentially expressed genes in the offspring’s prefrontal cortex were the targets of ASD-related transcription factors, including AR, ESR1, and RORA. The hypergeometric distribution analysis revealed that BPA may regulate the expression of such genes through these transcription factors in a sex-dependent manner. The molecular docking analysis of BPA and ASD-related transcription factors revealed novel potential targets of BPA, including RORA, SOX5, TCF4, and YY1. Our findings indicated that prenatal BPA exposure disrupts ASD-related genes in the offspring’s prefrontal cortex and may increase the risk of ASD through sex-dependent molecular mechanisms, which should be investigated further.

  19. Detection of REST expression in the testis using epitope-tag knock-in mice generated by genome editing. Peer-reviewed

    Ryuichi Kimura#, Yukiko U. Inoue#, Takako Kikkawa#, Misako Tatehana, Yuki Morimoto, Hitoshi Inada, Shinya Oki, Takayoshi Inoue, Noriko Osumi (#equally contribution)

    Developmental Dynamics　251　(3)　525-535　2021/09

  20. Sex differences in the effects of prenatal bisphenol A exposure on autism-related genes and their relationships with the hippocampus functions International-journal Peer-reviewed

    Surangrat Thongkorn, Songphon Kanlayaprasit, Pawinee Panjabud, Thanit Saeliw, Thanawin Jantheang, Kasidit Kasitipradit, Suthathip Sarobol, Depicha Jindatip, Valerie W. Hu, Tewin Tencomnao, Takako Kikkawa, Tatsuya Sato, Noriko Osumi, Tewarit Sarachana

    Scientific Reports　11　(1)　1241-1241　2021/01/13

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41598-020-80390-2 　

    eISSN： 2045-2322

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    <title>Abstract</title>Our recent study has shown that prenatal exposure to bisphenol A (BPA) altered the expression of genes associated with autism spectrum disorder (ASD). In this study, we further investigated the effects of prenatal BPA exposure on ASD-related genes known to regulate neuronal viability, neuritogenesis, and learning/memory, and assessed these functions in the offspring of exposed pregnant rats. We found that prenatal BPA exposure increased neurite length, the number of primary neurites, and the number of neurite branches, but reduced the size of the hippocampal cell body in both sexes of the offspring. However, in utero exposure to BPA decreased the neuronal viability and the neuronal density in the hippocampus and impaired learning/memory only in the male offspring while the females were not affected. Interestingly, the expression of several ASD-related genes (e.g. <italic>Mief2</italic>, <italic>Eif3h</italic>, <italic>Cux1</italic>, and <italic>Atp8a1</italic>) in the hippocampus were dysregulated and showed a sex-specific correlation with neuronal viability, neuritogenesis, and/or learning/memory. The findings from this study suggest that prenatal BPA exposure disrupts ASD-related genes involved in neuronal viability, neuritogenesis, and learning/memory in a sex-dependent manner, and these genes may play an important role in the risk and the higher prevalence of ASD in males subjected to prenatal BPA exposure.

  21. Paternal age affects offspring via an epigenetic mechanism involving REST/NRSF Peer-reviewed

    Kaichi Yoshizaki, Ryuichi Kimura, Hisato Kobayashi, Shinya Oki, Takako Kikkawa, Lingling Mai, Kohei Koike, Kentaro Mochizuki, Hitoshi Inada, Yasuhisa Matsui, Tomohiro Kono, Noriko Osumi

    EMBO reports　22　(2)　2021/01/05

    Publisher: EMBO

    DOI： 10.15252/embr.202051524 　

    ISSN： 1469-221X

    eISSN： 1469-3178

  22. Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/β-catenin, and mTOR signaling during corticogenesis International-journal Peer-reviewed

    Cristine R. Casingal, Takako Kikkawa, Hitoshi Inada, Yukio Sasaki, Noriko Osumi

    Molecular Brain　13　(1)　167-167　2020/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1186/s13041-020-00706-1 　

    eISSN： 1756-6606

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    <title>Abstract</title>Corticogenesis is one of the most critical and complicated processes during embryonic brain development. Any slight impairment in corticogenesis could cause neurodevelopmental disorders such as Fragile X syndrome (FXS), of which symptoms contain intellectual disability (ID) and autism spectrum disorder (ASD). Fragile X mental retardation protein (FMRP), an RNA-binding protein responsible for FXS, shows strong expression in neural stem/precursor cells (NPCs) during corticogenesis, although its function during brain development remains largely unknown. In this study, we attempted to identify the FMRP target mRNAs in the cortical primordium using RNA immunoprecipitation sequencing analysis in the mouse embryonic brain. We identified 865 candidate genes as targets of FMRP involving 126 and 118 genes overlapped with ID and ASD-associated genes, respectively. These overlapped genes were enriched with those related to chromatin/chromosome organization and histone modifications, suggesting the involvement of FMRP in epigenetic regulation. We further identified a common set of 17 FMRP “core” target genes involved in neurogenesis/FXS/ID/ASD, containing factors associated with Ras/mitogen-activated protein kinase, Wnt/β-catenin, and mammalian target of rapamycin (mTOR) pathways. We indeed showed overactivation of mTOR signaling via an increase in mTOR phosphorylation in the <italic>Fmr1</italic> knockout (<italic>Fmr1</italic> KO) neocortex. Our results provide further insight into the critical roles of FMRP in the developing brain, where dysfunction of FMRP may influence the regulation of its mRNA targets affecting signaling pathways and epigenetic modifications.

  23. Chronic brain histamine depletion in adult mice induced depression-like behaviours and impaired sleep-wake cycle. International-journal Peer-reviewed

    Yo Yamada, Takeo Yoshikawa, Fumito Naganuma, Takako Kikkawa, Noriko Osumi, Kazuhiko Yanai

    Neuropharmacology　175　108179-108179　2020/09/15

    DOI： 10.1016/j.neuropharm.2020.108179 　

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    Histamine acts as a neurotransmitter to regulate various physiological processes. Brain histamine is synthesized from an essential amino acid histidine in a reaction catalysed by histidine decarboxylase (Hdc). Hdc-positive neurons exist mainly in the tuberomammillary nucleus (TMN) of the posterior hypothalamus and project their axons to the entire brain. Recent studies have reported that a chronic decrease in histamine levels in the adult human brain was observed in several neurological disorders. However, it is poorly understood whether lower histamine levels play a causative role in those disorders. In the present study, we induced chronic histamine deficiency in the brains of adult mice to allow direct interpretation of the relationship between an impaired histaminergic nervous system and the resultant phenotype. To induce chronic brain histamine deficiency starting in adulthood, adeno-associated virus expressing Cre recombinase was microinjected into the TMN of Hdc flox mice (cKO mice) at the age of 8 weeks. Immunohistochemical analysis showed expression of Cre recombinase in the TMN of cKO mice. The reduction of histamine contents with the decreased Hdc expression in cKO brain was also confirmed. Behavioural studies revealed that chronic histamine depletion in cKO mice induced depression-like behaviour, decreased locomotor activity in the home cage, and impaired aversive memory. Sleep analysis showed that cKO mice exhibited a decrease in wakefulness and increase in non-rapid eye movement sleep throughout the day. Taken together, this study clearly demonstrates that chronic histamine depletion in the adult mouse brain plays a causative role in brain dysfunction.

  24. Dmrt genes participate in the development of Cajal‐Retzius cells derived from the cortical hem in the telencephalon Peer-reviewed

    Takako Kikkawa, Nobuyuki Sakayori, Hayato Yuuki, Yu Katsuyama, Fumio Matsuzaki, Daijiro Konno, Takaya Abe, Hiroshi Kiyonari, Noriko Osumi

    Developmental Dynamics　249　(6)　698-710　2020/02/12

    Publisher: Wiley

    DOI： 10.1002/dvdy.156 　

    ISSN： 1058-8388

    eISSN： 1097-0177

    More details Close

    Abstract Background During development, Cajal‐Retzius (CR) cells are the first generated and essential pioneering neurons that control neuronal migration and arealization in the mammalian cortex. CR cells are derived from specific regions within the telencephalon, that is, the pallial septum in the rostromedial cortex, the pallial‐subpallial boundary, and the cortical hem (CH) in the caudomedial cortex. However, the molecular mechanism underlying the generation of CR cell subtypes in distinct regions of origin is poorly understood. Results We found that double‐sex and mab‐3 related transcription factor (Dmrt) genes, that is, Dmrta1 and Dmrt3, were expressed in the progenitor domains that produce CR cells. The number of CH‐derived CR cells was severely decreased in Dmrt3 mutants, especially in Dmrta1 and Dmrt3 double mutants. The reduced production of the CR cells was consistent with the developmental impairment of the CH structures in the medial telencephalon from which the CR cells are produced. Conclusion Dmrta1 and Dmrt3 cooperatively regulate patterning of the CH structure and production of the CR cells from the CH during cortical development.

  25. The role of Pax6 in brain development and its impact on pathogenesis of autism spectrum disorder. International-journal Peer-reviewed

    Takako Kikkawa, Cristine R Casingal, Seung Hee Chun, Hiroshi Shinohara, Kotaro Hiraoka, Noriko Osumi

    Brain research　1705　95-103　2019/02/15

    DOI： 10.1016/j.brainres.2018.02.041 　

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    Pax6 transcription factor is a key player in several aspects of brain development and function. Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which several loci and/or genes have been suggested as causative candidate factors. Based on data obtained from meta-analyses of the transcriptome and ChIP analyses, we hypothesized that the neurodevelopmental gene PAX6 regulates and/or binds to a large number of genes (including many ASD-related ones) that modulate the fate of neural stem/progenitor cells and functions of neuronal cells, subsequently affecting animal behavior. Network analyses of PAX6/ASD-related molecules revealed significant clusters of molecular interactions involving regulation of cell-cell adhesion, ion transport, and transcriptional regulation. We discuss a novel function of Pax6 as a chromatin modulator that alters the chromatin status of ASD genes, thereby inducing diverse phenotypes of ASD and related neurodevelopmental diseases.

  26. Conserved and divergent functions of Pax6 underlie species-specific neurogenic patterns in the developing amniote brain. International-journal Peer-reviewed

    Wataru Yamashita, Masanori Takahashi, Takako Kikkawa, Hitoshi Gotoh, Noriko Osumi, Katsuhiko Ono, Tadashi Nomura

    Development (Cambridge, England)　145　(8)　pii: dev159764　2018/04/16

    DOI： 10.1242/dev.159764 　

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    The evolution of unique organ structures is associated with changes in conserved developmental programs. However, characterizing the functional conservation and variation of homologous transcription factors (TFs) that dictate species-specific cellular dynamics has remained elusive. Here, we dissect shared and divergent functions of Pax6 during amniote brain development. Comparative functional analyses revealed that the neurogenic function of Pax6 is highly conserved in the developing mouse and chick pallium, whereas stage-specific binary functions of Pax6 in neurogenesis are unique to mouse neuronal progenitors, consistent with Pax6-dependent temporal regulation of Notch signaling. Furthermore, we identified that Pax6-dependent enhancer activity of Dbx1 is extensively conserved between mammals and chick, although Dbx1 expression in the developing pallium is highly divergent in these species. Our results suggest that spatiotemporal changes in Pax6-dependent regulatory programs contributed to species-specific neurogenic patterns in mammalian and avian lineages, which underlie the morphological divergence of the amniote pallial architectures.

  27. Organizing activity of Fgf8 on the anterior telencephalon Peer-reviewed

    Tatsuya Sato, Takako Kikkawa, Tetsuichiro Saito, Keiichi Itoi, Noriko Osumi

    DEVELOPMENT GROWTH & DIFFERENTIATION　59　(9)　701-712　2017/12

    DOI： 10.1111/dgd.12411 　

    ISSN： 0012-1592

    eISSN： 1440-169X

  28. Gene tracing analysis reveals the contribution of neural crest-derived cells in pituitary development Peer-reviewed

    Hiroki Ueharu, Saishu Yoshida, Takako Kikkawa, Naoko Kanno, Masashi Higuchi, Takako Kato, Noriko Osumi, Yukio Kato

    Journal of Anatomy　230　(3)　373-380　2017/03

    Publisher: Wiley

    DOI： 10.1111/joa.12572 　

    ISSN： 0021-8782

  29. Electroporation in the rodent embryonic brain using whole embryo culture system Peer-reviewed

    Takako Kikkawa, Masanori Takahashi, Noriko Osumi

    Current Protocols in Neuroscience　2017　(3.30)　3.30.1-3.30.16　2017/01/01

    Publisher: Blackwell Publishing Inc.

    DOI： 10.1002/cpns.21 　

    ISSN： 1934-8576 1934-8584

  30. Regional Volume Decreases in the Brain of Pax6 Heterozygous Mutant Rats: MRI Deformation-Based Morphometry Peer-reviewed

    Kotaro Hiraoka, Akira Sumiyoshi, Hiroi Nonaka, Takako Kikkawa, Ryuta Kawashima, Noriko Osumi

    PLOS ONE　11　(6)　e0158153　2016/06

    DOI： 10.1371/journal.pone.0158153 　

    ISSN： 1932-6203

  31. Maternal Dietary Imbalance between Omega-6 and Omega-3 Polyunsaturated Fatty Acids Impairs Neocortical Development via Epoxy Metabolites Peer-reviewed

    Nobuyuki Sakayori, Takako Kikkawa, Hisanori Tokuda, Emiko Kiryu, Kaichi Yoshizaki, Hiroshi Kawashima, Tetsuya Yamada, Hiroyuki Arai, Jing X. Kang, Hideki Katagiri, Hiroshi Shibata, Sheila M. Innis, Makoto Arita, Noriko Osumi

    STEM CELLS　34　(2)　470-482　2016/02

    DOI： 10.1002/stem.2246 　

    ISSN： 1066-5099

    eISSN： 1549-4918

  32. Preparation of Rat Serum Suitable for Mammalian Whole Embryo Culture Peer-reviewed

    Masanori Takahashi, Sayaka Makino, Takako Kikkawa, Noriko Osumi

    JOVE-JOURNAL OF VISUALIZED EXPERIMENTS　90　(90)　e51969　2014/08

    DOI： 10.3791/51969 　

    ISSN： 1940-087X

  33. Asymmetric inheritance of Cyclin D2 maintains proliferative neural stem/progenitor cells: A critical event in brain development and evolution Peer-reviewed

    Yuji Tsunekawa, Takako Kikkawa, Noriko Osumi

    DEVELOPMENT GROWTH & DIFFERENTIATION　56　(5)　349-357　2014/06

    DOI： 10.1111/dgd.12135 　

    ISSN： 0012-1592

    eISSN： 1440-169X

  34. Dmrta1 regulates proneural gene expression downstream of Pax6 in the mammalian telencephalon Peer-reviewed

    Takako Kikkawa, Takeshi Obayashi, Masanori Takahashi, Urara Fukuzaki-Dohi, Keiko Numayama-Tsuruta, Noriko Osumi

    GENES TO CELLS　18　(8)　636-649　2013/08

    DOI： 10.1111/gtc.12061 　

    ISSN： 1356-9597

  35. The role of the transcription factor pax6 in brain development and evolution: Evidence and hypothesis Peer-reviewed

    Noriko Osumi, Takako Kikkawa

    Cortical Development: Neural Diversity and Neocortical Organization　43-62　2013/01/01

    Publisher: Springer Japan

    DOI： 10.1007/978-4-431-54496-8_3 　

  36. Reduced proliferation and excess astrogenesis of Pax6 heterozygous neural stem/progenitor cells Peer-reviewed

    Nobuyuki Sakayori, Takako Kikkawa, Noriko Osumi

    NEUROSCIENCE RESEARCH　74　(2)　116-121　2012/10

    DOI： 10.1016/j.neures.2012.08.004 　

    ISSN： 0168-0102

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Misc. 19

  1. ゲノム編集を用いたPA標識マウスによるREST/NRSF局在動態の観察

    大隅典子, 井上(上野)由紀子, 舘花美沙子, 吉川貴子, 稲田仁, 井上高良

    日本解剖学会総会・全国学術集会抄録集(CD-ROM)　128th　2023

  2. マウス精子形成過程におけるREST/NRSFの発現動態の変化 新生仔から成体まで

    舘花美沙子, Mains-Sheard John, 稲田仁, 吉川貴子, 大隅典子

    DOHad研究(Web)　10　(2)　2022

    ISSN： 2187-2597

  3. 有胎盤類特有のzip code配列獲得による放射状グリア細胞内mRNA輸送機構の進化

    吉川貴子, 若松義雄, 井上(上野)由紀子, 鈴木久仁博, 井上高良, 大隅典子

    日本解剖学会総会・全国学術集会講演プログラム・抄録集　127th (CD-ROM)　2022

  4. Expression Changes of REST/NRSF in Spermatogenesis from Neonatal to Adult Murine Testis

    MAINS-SHEARD John, TATEHANA Misako, INADA Hitoshi, INADA Hitoshi, KIKKAWA Takako, KIMURA Ryuichi, INOUE Yukiko, MORIMOTO Yuki, OKI Shinya, INOUE Takayoshi, OSUMI Noriko

    日本分子生物学会年会プログラム・要旨集(Web)　44th　2021

  5. 哺乳類の終脳初期発生過程におけるPax6下流因子δカテニンの機能解析

    眞鍋柊, CHUN Seung Hee, 越智翔平, 吉川貴子, 大隅典子

    日本分子生物学会年会プログラム・要旨集(Web)　43rd　2020

  6. CyclinD2のmRNA輸送による有胎盤類大脳皮質の拡大機構の解明

    吉川貴子, 若松義雄, 井上(上野)由紀子, 鈴木久仁博, 井上高良, 大隅典子

    日本解剖学会総会・全国学術集会講演プログラム・抄録集　125th　2020

  7. 染色体整列因子CAMP(CHAMP1)欠損による知的障害発症メカニズムの解明

    永井正義, 永井正義, 家村顕自, 服部聡子, 吉川貴子, 萩原英雄, 安澤隼人, 木下賢吾, 大隅典子, 宮川剛, 田中耕三

    日本分子生物学会年会プログラム・要旨集(Web)　42nd　2019

  8. PATERNAL AGE AFFECTS OFFSPRING'S BEHAVIOR POSSIBLY VIA EPIGENETIC MECHANISM RECRUITING A TRANSCRIPTIONAL REPRESSOR REST

    Kaichi Yoshizaki, Ryuichi Kimura, Kentaro Mochizuki, Takako Kikkawa, Hitoshi Inada, Niroko Osumi

    EUROPEAN NEUROPSYCHOPHARMACOLOGY　29　S831-S831　2019

    DOI： 10.1016/j.euroneuro.2017.08.089 　

    ISSN： 0924-977X

    eISSN： 1873-7862

  9. 精子におけるエピゲノム修飾と次世代への影響

    大隅 典子, 木村 龍一, Mai Lingling, 舘花 美沙子, 吉川 貴子, 望月 研太郎, 稲田 仁

    DOHaD研究　8　(3)　30-30　2019

    Publisher: 日本DOHaD学会事務局

    ISSN： 2187-2597

  10. CRISPR/Cas9ゲノム編集技術を用いた大脳皮質発生過程における放射状グリア細胞内Cyclin D2 mRNA輸送機構の解析

    吉川 貴子, 井上 由紀子, 野, 井上 高良, 大隅 典子

    生命科学系学会合同年次大会　2017年度　[2LBA-083]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  11. 哺乳類終脳の初期発生におけるPax6下流遺伝子delta-cateninの機能解析

    錢 昇希, 吉川 貴子, 大隅 典子

    生命科学系学会合同年次大会　2017年度　[3LBA-129]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  12. マウス胎児脳における染色体整列因子CAMPの発現部位の同定

    永井 正義, 家村 顕自, 吉川 貴子, 大隅 典子, 田中 耕三

    生命科学系学会合同年次大会　2017年度　[3LBA-131]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  13. 父加齢が次世代の行動に影響を与えるエピジェネティックなメカニズム:新たな自閉スペクトラム症モデルの提案

    吉崎嘉一, 小池佐, 木村龍一, 吉川貴子, 沖真弥, 沖真弥, 稲田仁, 松居靖之, 河野友宏, 大隅典子

    日本解剖学会総会・全国学術集会講演プログラム・抄録集　122nd　2017

  14. Pax6はほ乳類大脳皮質内抑制性ニューロンの産生に関与する

    中村 龍司, 吉川 貴子, 佐藤 達也, 大隅 典子

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　88回・38回　[2P1040]-[2P1040]　2015/12

    Publisher: (公社)日本生化学会

  15. Pax6 is a neural/stem progenitor cell fate determinant

    251　(12)　1118-1122　2014/12/27

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  16. Molecular and cellular mechanisms of cortical development: its significance in brain evolution and psychiatric diseases

    Y. Tsunekawa, T. Kikkawa, N. Osumi

    JOURNAL OF NEUROCHEMISTRY　130　8-8　2014/08

    ISSN： 0022-3042

    eISSN： 1471-4159

  17. 放射状グリア細胞のCyclin D2mRNA輸送におけるFMRPの役割

    YOON Jeonghyeon, 吉川貴子, 大隅典子

    日本分子生物学会年会プログラム・要旨集(Web)　37th　WEB ONLY 1P-0664　2014

  18. Dmrtファミリー遺伝子は大脳皮質発生過程における初期ニューロン分化を制御する

    吉川貴子, 高橋将文, 勝山裕, 大隅典子

    日本動物学会大会予稿集　84th　39　2013/08/12

  19. Dmrta1, a downstream of Pax6, regulates Neurogenin2 expression in the mammalian telencephalon

    Takako Kikkawa, Masanori Takahashi, Yu Katsuyama, Noriko Osumi

    NEUROSCIENCE RESEARCH　71　E331-E331　2011

    DOI： 10.1016/j.neures.2011.07.1447 　

    ISSN： 0168-0102

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Books and Other Publications 9

  1. 脳科学辞典「放射状グリア細胞」

    吉川貴子, 大隅典子

    脳科学辞典　2021

  2. 東北医学雑誌「大脳皮質発生過程の神経幹細胞内mRNA輸送機構の研究」

    吉川貴子

    東北医学会　2020

  3. 脳神経系の再生医学 -発生と再生の融合的新展開-

    大隅典子, 吉川貴子

    診断と治療社　2015

  4. 脳科学辞典「PAX遺伝子群」

    櫻井勝康, 吉川貴子, 大隅典子

    脳科学辞典　2014

  5. 週刊 医学のあゆみ

    吉川貴子, 大隅典子(範囲:Pax6による神経幹細胞の分化制御」 251(12, 13) , 1118-1122)

    医歯薬出版株式会社　2014

  6. NEUROMETHODS: Electroporation Methods and Neuroscience

    Takahashi, M, Kikkawa, T, Osumi, N

    Springer　2014

  7. Cortical development: Neural Diversity and Neocortical Organization

    Osumi, N, Kikkawa, T

    Springer　2013

  8. 脳科学辞典「全胚培養」

    吉川貴子, 大隅典子

    脳科学辞典　2012

  9. シグナル伝達キーワード辞典

    吉川貴子, 大隅典子

    羊土社　2012

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Presentations 10

  1. 放射状グリア細胞における細胞周期因子Cyclin D2のmRNA輸送機構の解析：有胎盤類の大脳皮質拡大に寄与する可能性

    吉川貴子, 若松義雄, 井上-上野由紀子, 鈴木久仁博, 井上高良, 大隅典子

    日本解剖学会 第67回東北・北海道連合支部学術集会　2021/09/05

  2. 胎生期の神経前駆細胞内におけるmRNA調節メカニズム Invited

    吉川貴子, Cristine Casingal, Sharmin Naher, 井上-上野由紀子, 井上高良, 大隅典子

    NPBPPP 2020合同年会

  3. mRNA transport of Cyclin D2 in radial glial cells during brain development. International-presentation

    Kikkawa, T.

    The 5th German-Japanize Retreat on Forebrain Development　2020/01/14

  4. Dmrt genes control the development of Cajal-Retzius cells derived from specific origins in the cerebral cortex.

    Kikkawa, T, Sakayori, N, Yuuki, H, Osumi, N

    第41回 日本神経科学大会　2018/07/26

  5. Basally matters during corticogenesis. International-presentation

    Kikkawa, T

    The 4th German-Japanize Retreat on Forebrain Development　2017/09/12

  6. Dmrt genes control the development of Cajal-Retzius cells derived from specific origins in the cerebral cortex. International-presentation Invited

    Takako Kikkawa

    The 8th symposium of Korean Society for Developmental Neurobiologists　2016/07/08

  7. Dmrt genes differentially participate in Cajal-Retzius cell development of the cerebral cortex. International-presentation

    Kikkawa, T, Sakayori, N, Yuuki, H, Kastuyama, Y, Osumi, N

    Tohoku Forum for Creativity, Frontiers of Brain Science, Symposium on Development and Disease　2015/08/24

  8. Dmrtファミリー遺伝子は大脳皮質発生過程における初期ニューロン分化を制御する Invited

    吉川貴子, 高橋将文, 勝山裕, 大隅典子

    第84回 日本動物学会　2013/09/26

  9. The doublesex homolog Dmrta1 regulates the production of early-born neurons in the mammalian cerebral cortex International-presentation Invited

    Kikkawa, T, Takahashi, M, Katsuyama, Y, Osumi, N

    Neuro 2013 Satellite Symposium Molecular and Cellular Mechanisms of Brain Development and Evolution　2013/06/09

  10. 大脳皮質発生過程におけるDmrta1の機能解析

    吉川 貴子

    第6回 神経発生討論会　2013/03/14

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Research Projects 24

  1. 脆弱X症候群とプラダー・ウィリー症候群の間を繋ぐインプリンティング機構の解明

    吉川貴子, 越智翔平

    Offer Organization: AMED

    System: 脳神経科学統合プログラム

    2024/09 - 2027/03

  2. Understanding sex differences in behavior and underlying neurodevelopmental mechanisms using mouse models of neurodevelopmental disorders

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2024/04 - 2027/03

  3. 脳発生過程のモータータンパク質機能不全による小頭症発症機構の解明

    吉川 貴子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(C)

    Category: 基盤研究(C)

    Institution: 東北大学

    2023/04 - 2026/03

  4. 非アルツハイマー型認知症のバイオマーカー、治療標的、リスク因子の探索

    吉川 貴子, 中村 昭範, 山本 由似

    Offer Organization: AMED

    System: 戦略的国際共同研究プログラム（SICORP）日・オーストラリア共同研究

    2023/09 - 2025/12

  5. 妊娠中の脂肪酸摂取が仔の摂食行動を制御する新規メカニズムの解明

    酒寄 信幸, 有田 誠, 吉川 貴子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(B)

    Category: 基盤研究(B)

    Institution: 広島大学

    2021/04 - 2025/03

  6. 神経発達障害を引き起こすmRNA 制御機構の解明

    Offer Organization: 持田記念医学薬学振興財団

    System: 研究助成金

    2023/11 - 2024/12

  7. なぜX精子の産生がY精子より少ないのかに関する分子機構解明

    大隅 典子, 稲田 仁, 吉川 貴子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 挑戦的研究(萌芽)

    Category: 挑戦的研究(萌芽)

    Institution: 東北大学

    2022/06 - 2024/03

  8. 神経発達障害の性差を生み出す脳発生プログラムの解明

    吉川貴子

    Offer Organization: 東北大学

    System: 学際科学フロンティア研究所 領域創成研究プログラム

    2022/06 - 2024/03

  9. 胎生脳のmRNA調節機構を基盤とした脆弱X症候群の病態解明

    吉川 貴子

    Offer Organization: 武田科学振興財団

    System: 医学系研究助成

    2022 - 2024

  10. 非アルツハイマー型認知症のバイオマーカー、治療標的、リスク因子の探索

    香川 慶輝, 中村 昭範, 山本 由似, 吉川 貴子

    Offer Organization: AMED

    System: 戦略的国際共同研究プログラム（SICORP）日・オーストラリア共同研究

    2023 - 2023/08

  11. 細胞内mRNA輸送による有胎盤類の大脳皮質拡大メカニズムの解明

    吉川 貴子, 若松 義雄

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(C)

    Category: 基盤研究(C)

    Institution: 東北大学

    2020/04 - 2023/03

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    大脳皮質の発生過程では、放射状グリア細胞（radial glia; RG）と呼ばれる神経幹細胞が予め決められたタイミングで増殖・分化し、多様な神経細胞が産生される。RG細胞は脳表面（基底膜側）まで非常に長い放射状の突起を伸ばしており、基底膜側突起を受け継いだ娘細胞はRG細胞として未分化性を維持することが知られている。我々はこれまでに、細胞周期のG1期からS期への移行を促進するCyclinD2のmRNAおよびタンパク質が、RG細胞の基底膜側突起の末端部まで輸送されること、さらにCyclinD2 mRNAの3´UTR領域に輸送に必要な約50 bpの配列があることを明らかにしていた（Tsunekawa et al., EMBO J, 2012）。さらに我々は、ゲノム編集技術CRISPR/Cas9法によりCyclinD2 mRNA輸送配列を欠失させたマウスのRG細胞において、CyclinD2 mRNA輸送が阻害されることを見出している（吉川ら未発表）。今年度は、このCyclinD2 mRNA輸送阻害マウスと野生型マウスを用いて大脳皮質原基の細胞増殖の測定を行った。その結果、転写因子Tbr2を発現する中間増殖細胞の増殖が、CyclinD2輸送阻害マウスで低下していた。また、マウス型の3´UTR を含むCyclinD2をマウスに強制発現したところ、これらの細胞集団が存在するsubventricular zoneにおいて細胞増殖の増加が認められたことから、CyclinD2が特定の細胞集団の増殖性を制御する可能性が示唆された。

  12. Sex Differences In Regulation Of FMRP mRNA Targets During Brain Development

    吉川 貴子

    Offer Organization: 日本科学協会

    System: 笹川科学研究 海外発表促進助成

    2023 -

  13. Sex Differences in Pax6-FMRP Feedback Regulation Mechanisms in Neurogenesis

    OSUMI Noriko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2019/04 - 2022/03

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    To understand how sex differences in brain morphology and incidence of brain diseases arise during brain development, this study focused on Pax6, a transcriptional regulator of neurogenesis, and FMRP, a causative factor of severe mental retardation. Using embryonic mouse brain samples, we identified target mRNAs of the RNA-binding protein FMRP and integrated them with RNA-seq data from the embryonic cortical primordium, where neurogenesis is actively occurring, to identify genes that show sex differences in their expression levels. From the results obtained, we identified FMRP target mRNAs that are differentially expressed in males and females, and identified FMRP regulatory molecules other than Pax6 that show sex differences.

  14. Basal transport of Ccnd2 mRNA in radial glial cells is important for the production of basal progenitors in the developing mouse cortex.

    2022 -

  15. 大脳皮質発生過程の分子機構の解明

    吉川貴子

    Offer Organization: 東北大学 杜の都女性研究者エンパワーメント推進事業

    System: ネクストステップ研究費

    2019/04 - 2020/03

  16. Mechanism of RNA transport and localization in neural stem cells during corticogenesis

    Kikkawa Takako

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists

    Category: Grant-in-Aid for Early-Career Scientists

    Institution: Tohoku University

    2018/04 - 2020/03

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    During corticogenesis, neural stem/progenitor cells need to adequately proliferate and differentiate to various types of neurons. Neural stem/progenitor cells in the developing cortex are called radial glial (RG) cells, as they possess highly polarized morphology with long apical/basal processes. We have previously shown in the mouse that mRNAs of CyclinD2, coding a cell cycle regulator, are transported to the basal end-foot of the RG cell. We found that the thickness of the cortex was decreased in the CyclinD2 mRNA transport element-deleted mutant mice that CyclinD2 mRNA no longer localized in the basal end-feet of RG cells, yet remained around the RG cell soma. These results suggest that CyclinD2 mRNA transport in RG cells is important to make the cortex during embryogenesis.

  17. Development of mRNA transportation mechanisms in neural stem/progenitor cells during evolution

    Kikkawa Takako

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Tohoku University

    2016/04 - 2018/03

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    During cortical development in mammals, neural stem/progenitor cells need to adequately proliferate and differentiate. Neural progenitor cells during corticogenesis are called radial glial (RG) cells because they show highly polarized morphology with long and thin processes. We have previously shown that mRNA of Cyclin D2 encoding a cell cycle regulator is transported to the basal end-foot of RG cells by the specific mRNA transportation element. We applied a CRISPR/Cas9 genome editing system in mouse embryos and selectively removed the element. We found that the mutant mice show inhibition of Cyclin D2 mRNA transportation to the basal end-foot of RG cells. These results suggest involvement of the mammalian specific cis-regulatory sequence of Cyclin D2 mRNA in the mRNA transportation to the basal end-foot of RG cells.

  18. The role of RNA-binding protein for long-distance transportation of mRNA within embryonic neural progenitor cells

    OSUMI Noriko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2014/04 - 2017/03

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    The mammalian cortex has expanded during evolution and its primordium consists with radial glial (RG) cells as neural progenitors. RG cells have long processes stretching between apical and basal surface of the cortical primordium. We would like to understand molecular mechanisms for long-distance transportation within the RG cell, and focused on an RNA-binding protein, i.e., fragile X mental retardation protein (FMRP) , coded by Fmr1 gene. We performed RIP-ChIP analyses and found candidate mRNAs as targets of FMRP, and examined expression profiles of the candidate genes. Immunohistochemical analyses showed decreased expression of some of the candidate genes at the protein level, suggesting a possibility that these transcripts can be transported by FMRP.

  19. Competitive

    吉川 貴子

    Offer Organization: 東北大学 杜の都女性研究者エンパワーメント推進事業

    System: 英文校閲費用補助制度

    2017 -

  20. 哺乳類型の大脳皮質を構築する分子基盤の解明 Competitive

    吉川 貴子

    Offer Organization: 日本科学協会

    System: 笹川科学研究助成

    2015 -

  21. 大脳皮質の時期特異的な神経細胞分化におけるDmrtファミリー遺伝子の機能解析

    吉川 貴子

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特別研究員奨励費

    Category: 特別研究員奨励費

    Institution: 東北大学

    2012 - 2013

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    哺乳類の大脳皮質は神経細胞の構築から6層構造を呈し、各層には異なった投射パターンや遺伝子発現を持つ興奮性ニューロンが配置されるが、どの層のニューロンになるかという細胞運命の決定は、それぞれのニューロンが産生された時期に依存する。Dmrtファミリーは、特に初期の神経細胞に分化する運命の神経幹細胞に発現が強いことから、大脳皮質神経細胞の時期特異的な分化に関与していると考えられ、それによって大脳皮質の層構造形成や皮質ニューロンの多様性分化にも影響を与えている可能性がある。そこで、大脳皮質においてもっとも早く分化する神経細胞であるカハール・レチウス細胞について詳細に検討した。Dmrta1は大脳皮質原基において、カハール・レチウス細胞を生み出す領域に発現し、Dmrta1ノックアウト(KO)マウスにおいてReelin陽性カハール・レチウス細胞が野生型胚と比較して減少していることを明らかにした。Dmrta1の下流遺伝子を探索するために、野生型およびDmrta1KOマウスのE10.5日胚の終脳を用いてマイクロアレイ解析を行ったところ(n=2)、大脳皮質に発現が認められるdiaphanous homolog 3 (Diap3)、ribonuclease H2 subunit B (Rnaseh2b)、solute carrier family 9 member 3 regulator1 (Slc9a3r1)、cyclin-dependent kinase inhibitor 1C (Cdkn1c ; p57^<KIP2>)の発現量がDmrta1 KOマウスにおいて減少していた。さらにDmrt3がDmrta1と重複して大脳皮質に発現が観察されることから(Kikkawa et al.,2013)、Dmrta1とDmrt3の機能重複によってDmrta1 KO胚において脳発生の異常が明瞭でない可能性がある。そこで理化学研究所発生・再生科学総合センターの松崎文雄グループリーダーとの共同研究により、Dmrt3 KOマウスにおいてもReelin陽性カハール・レチウス細胞の減少が認められるという結果を得た。

  22. 終脳発生過程におけるPax6下流遺伝子Dmrta1の機能解析 Competitive

    吉川 貴子

    Offer Organization: 東北大脳科学グローバルCOE

    System: 特別研究奨励費

    2011/04 - 2012/03

  23. 終脳発生過程におけるPax6下流遺伝子Dmrta1の機能解析 Competitive

    吉川 貴子

    Offer Organization: 東北大学 大学院医学系研究科

    System: スターター助成

    2010/04 - 2011/03

  24. 終脳発生過程におけるPax6下流遺伝子Dmrta1の機能解析 Competitive

    吉川 貴子

    Offer Organization: 東北大脳科学グローバルCOE

    System: 特別研究奨励費

    2010/04 - 2011/03

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Teaching Experience 4

  1. 解剖学・生理学序説　東北大学

  2. 発生学　東北大学

  3. 基礎ゼミ　東北大学

  4. 脳解剖学　東北大学

Social Activities 3

  1. 公開講演会「脳の性差が生まれる仕組み―神経発達障害の性差―」

    2023/09/22 -

  2. サイエンスカフェ 「脳はいかにしてつくられるか」

    2013/10/05 -

  3. 第5回脳カフェ 「杜の都で脳を語るー脳はなぜ美に魅せられるのかー」

    2010/07/03 -

Media Coverage 4

  1. 小頭症を引き起こす新規原因分子を発見 胎仔脳の発生過程でのモーター分子の新たな機能

    東北大学　プレスリリース

    2024/12/05

  2. 父親の加齢で精子の質が変化する 加齢マウス精子のマイクロRNA変化と次世代の神経発達障害リスク

    東北大学　プレスリリース

    2023/12/08

  3. 父親の加齢が子どもの発達障害の発症に影響する -マウス加齢モデルにおける精子DNA低メチル化が鍵-

    東北大学　プレスリリース

    2021/01/06

  4. 指定難病脆弱X症候群発症の新たな分子メカニズムの解明 胎仔脳での特定分子経路の活性化が原因の可能性

    東北大学　プレスリリース

    2020/12/16