Dlx4 gene co-option in mammalian vomeronasal organ evolution

• Project/Area Number: 18H02490
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 45020:Evolutionary biology-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Sumiyama Kenta 国立研究開発法人理化学研究所, 生命機能科学研究センター, チームリーダー (00370114)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: エンハンサー進化 / 鋤鼻器 / ゲノム編集 / Dlx遺伝子群 / エンハンサーノックアウト / エンハンサー / Dlx3-4遺伝子 / ノックアウトマウス / Dlx4遺伝子 / 発現制御 / 進化 / 発生 / Dlx遺伝子 / 遺伝子コオプション進化 / ゲノム編集マウス

Outline of Final Research Achievements

We identified a non-coding region (enhancer) that regulates the expression of the Dlx3/Dlx4 gene, which is thought to play an important role in the unknown developmental process of the vomeronasal organ. Knockout mice lacking this region created by genome editing have been shown to completely lose Dlx3/Dlx4 gene expression in the vomeronasal organ. This vomeronasal organ-specific gene expression-deficient mouse will be an important resource for future vomeronasal organ development and functional studies. This tissue-specific gene knockout mouse production method by enhancer deletion is a technical achievement that can be applied to all other functional gene studies.

Academic Significance and Societal Importance of the Research Achievements

鋤鼻器の発生におけるDlx3/Dlx4遺伝子の発現調節を担うエンハンサーを明らかにしたことにより、多くの哺乳類で重要な役割を持ちながらヒトでは機能が失われた鋤鼻器発生の進化をゲノムレベルで研究する基礎を築いた。またエンハンサー欠失による組織特異的遺伝子ノックアウトマウス作製法は、従来の費用と時間のかかる条件付きノックアウトマウス作製法よりはるかに簡便であり、個体レベルでのあらゆる遺伝子機能研究の迅速効率化に貢献する重要な成果である。

Research Products

• [Journal Article] Visualization of Spatially-Controlled Vasospasm by Sympathetic Nerve-Mediated ROCK Activation. (2021)
  • Author(s): Ayako Imanishi, Hiroshi Ichise, Chuyun Fan, Yasuaki Nakagawa, Koichiro Kuwahara, Kenta Sumiyama, Michiyuki Matsuda, Kenta Terai.
  • Journal Title: Am J Phathol Volume: 191(1) Issue: 1 Pages: 194-203
  • DOI: 10.1016/j.ajpath.2020.09.012
  • Peer Reviewed / Open Access
• [Journal Article] A human isogenic iPSC-derived cell line panel identifies major regulators of aberrant astrocyte proliferation in Down syndrome (2021)
  • Author(s): Kawatani Keiji、Nambara Toshihiko、Nawa Nobutoshi、Yoshimatsu Hidetaka、Kusakabe Haruna、Hirata Katsuya、Tanave Akira、Sumiyama Kenta、Banno Kimihiko、Taniguchi Hidetoshi、Arahori Hitomi、Ozono Keiichi、Kitabatake Yasuji
  • Journal Title: Communications Biology Volume: 4 Issue: 1 Pages: 730-730
  • DOI: 10.1038/s42003-021-02242-7
  • Peer Reviewed / Open Access
• [Journal Article] Biliverdin Reductase-A Deficiency Brighten and Sensitize Biliverdin-binding Chromoproteins (2020)
  • Author(s): Kobachi Kenju、Kuno Sota、Sato Shinya、Sumiyama Kenta、Matsuda Michiyuki、Terai Kenta
  • Journal Title: Cell Structure and Function Volume: 45 Issue: 2 Pages: 131-141
  • DOI: 10.1247/csf.20010
  • NAID: 130007889516
  • Peer Reviewed / Open Access
• [Journal Article] Gsx2 is required for specification of neurons in the inferior olivary nuclei from Ptf1a-expressing neural progenitors in zebrafish. (2020)
  • Author(s): Itoh T, Takeuchi M, Sakgami M, Asakawa K, Sumiyama K, Kawakami K, Shimizu T, Hibi M.
  • Journal Title: Development Volume: 147
  • DOI: 10.1242/dev.190603
  • Peer Reviewed / Open Access
• [Journal Article] The regulatory landscape of the Dlx gene system in branchial arches: shared characteristics among Dlx bigene clusters and evolution (2020)
  • Author(s): Sumiyama Kenta、Tanave Akira
  • Journal Title: Development, Growth & Differentiation Volume: - Issue: 5 Pages: 355-362
  • DOI: 10.1111/dgd.12671
  • Peer Reviewed / Open Access
• [Journal Article] Booster, a Red-Shifted Genetically Encoded F?rster Resonance Energy Transfer (FRET) Biosensor Compatible with Cyan Fluorescent Protein/Yellow Fluorescent Protein-Based FRET Biosensors and Blue Light-Responsive Optogenetic Tools (2020)
  • Author(s): Watabe Tetsuya、Terai Kenta、Sumiyama Kenta、Matsuda Michiyuki
  • Journal Title: ACS Sensors Volume: 5 Issue: 3 Pages: 719-730
  • DOI: 10.1021/acssensors.9b01941
  • Peer Reviewed
• [Journal Article] Mark1 regulates distal airspace expansion through type I pneumocyte flattening in lung development (2019)
  • Author(s): Fumoto Katsumi、Takigawa-Imamura Hisako、Sumiyama Kenta、Yoshimura Shige H.、Maehara Natsumi、Kikuchi Akira
  • Journal Title: Journal of Cell Science Volume: 132 Issue: 24
  • DOI: 10.1242/jcs.235556
  • Peer Reviewed
• [Journal Article] FRET-assisted photoactivation of flavoproteins for in vivo two-photon optogenetics (2019)
  • Author(s): Kinjo Tomoaki、Terai Kenta、Horita Shoichiro、Nomura Norimichi、Sumiyama Kenta、Togashi Kaori、Iwata So、Matsuda Michiyuki
  • Journal Title: Nature Methods Volume: 16 Issue: 10 Pages: 1029-1036
  • DOI: 10.1038/s41592-019-0541-5
  • Peer Reviewed / Open Access
• [Journal Article] ゲノム編集技術を用いたDlx遺伝子群機能解析 (2019)
  • Author(s): 田邉彰、隅山健太
  • Journal Title: Medical Science Digest Volume: 9 Pages: 50-51
• [Journal Article] A platform of BRET-FRET hybrid biosensors for optogenetics, chemical screening, and in vivo imaging. (2018)
  • Author(s): Komatsu N, Terai K, Imanishi A, Kamioka Y, Sumiyama K, Jin T, Okada Y, Nagai T, Matsuda M.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 8984-8984
  • DOI: 10.1038/s41598-018-27174-x
  • NAID: 120006523820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Composite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine (2018)
  • Author(s): Muta Yu、Fujita Yoshihisa、Sumiyama Kenta、Sakurai Atsuro、Taketo M. Mark、Chiba Tsutomu、Seno Hiroshi、Aoki Kazuhiro、Matsuda Michiyuki、Imajo Masamichi
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 2174-2174
  • DOI: 10.1038/s41467-018-04527-8
  • NAID: 120006488609
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oocyte all-surfaces’ imaging method using micro-scale rotational flow (2018)
  • Author(s): Yalikun Yaxiaer、Aishan Yusufu、Mosha Abulaiti、Sumiyama Kenta、Tanaka Yo
  • Journal Title: Micro & Nano Letters Volume: 13 Issue: 3 Pages: 306-311
  • DOI: 10.1049/mnl.2017.0731
  • Peer Reviewed
• [Presentation] 鋤鼻器のDlx3 /Dlx4 遺伝子発現に必須なシス調節モジュールクラスターの発見 (2021)
  • Author(s): 田邉 彰、隅山 健太
  • Organizer: 日本遺伝学会第93回大会（オンライン）
• [Presentation] 遺伝子機能欠損をパラログ遺伝子の活性化で補償する (2020)
  • Author(s): 隅山 健太、田邉 彰
  • Organizer: Online MM meeting 2020、京都大学医学部
• [Presentation] Triple-target CRISPR enabled almost perfect whole-body bi-allelic knockouts at first generation (2019)
  • Author(s): Kenta Sumiyama, Genshiro Sunagawa, Maki Ukai-Tadenuma, Perrin Dimitri, Hiroki Ueda
  • Organizer: The 15th Transgenic Technology Meeting (TT2019)
  • Int'l Joint Research
• [Presentation] Cis-regulatory mechanism and evolution of mammalian Dlx gene clusters (2019)
  • Author(s): Kenta Sumiyama
  • Organizer: 52nd JSDB Annual Meeting
  • Int'l Joint Research / Invited
• [Presentation] 頭顔面形態形成を規定するDlx遺伝子群の発現パターンを進化機構に則って変更する試み (2019)
  • Author(s): 隅山 健太
  • Organizer: 第9回 Tokyo Vertebrate Morphology Meeting
• [Presentation] 脊椎動物形態形成遺伝子発現調節機構の進化：Dlx 遺伝子群を例に (2019)
  • Author(s): 隅山 健太
  • Organizer: 日本遺伝学会第91 回大会
  • Invited
• [Presentation] Triple-target CRISPR enabled production of complete bi-allelic double and triple gene knockouts (2019)
  • Author(s): Kenta Sumiyama, Hiroki Ueda
  • Organizer: Frontiers in Genome Engineering 2019
  • Int'l Joint Research
• [Presentation] トリプルCRISPR法による交配無しでのダブルノックアウト、トリプルノックアウトマウス作製 (2019)
  • Author(s): 田邉 彰、隅山 健太
  • Organizer: 大阪大学大学院医学系研究科 第12回若手研究フォーラム
• [Presentation] Inferring ancestral state before WGD from enhancers and CTCF/cohesin loops in developmental genes (2018)
  • Author(s): Kenta Sumiyama
  • Organizer: SMBE 2018
  • Int'l Joint Research
• [Presentation] ゲノム重複前の脊椎動物形質を推定する試み (2018)
  • Author(s): 隅山 健太
  • Organizer: 第８回 Tokyo Vertebrate Morphology Meeting
• [Presentation] ゲノム重複前の脊椎動物表現型を推定する新しい試み (2018)
  • Author(s): 隅山 健太
  • Organizer: 日本進化学会第20回大会
• [Book] 図解 人類の進化 猿人から原人、旧人、現生人類へ (2021)
  • Author(s): 斎藤 成也、海部 陽介、米田 穣、隅山 健太
  • Total Pages: 272
  • Publisher: 講談社
  • ISBN: 9784065261361