Mechanism of cell death suppression by Ptch1 and XIAP during mouse embryogenesis

• Project/Area Number: 17K08513
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General anatomy (including histology/embryology)
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: aoto kazushi 浜松医科大学, 医学部, 助教 (60360476)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ソニックヘッジホッグ(Shh)シグナル伝達経路 / patched1 / 脳神経管の細胞死抑制 / CRISPR-Cas9法 / GONAD法 / XIAP / エレクトロポレーション / 繊毛 / 変異マウス / Ptch1 / 細胞死抑制機構 / HA tag ノックインマウス / CRISPR-Cas9 / プロテオーム解析 / 細胞死抑制メカニズム / 線毛

Outline of Final Research Achievements

To analyze physiological function of inhibiting cell death oy Ptch1-XIAP association, we generated mutant mice of XIAP binding site with Ptch1 C terminus. But that Ptch1-dIBS mice did not show any phenotype. However, We also generated knock-in mice of two HA tag (2xHA) in Ptch1 C terminal, which are able to observe Ptch1-2xHA localization in cilia.

Academic Significance and Societal Importance of the Research Achievements

ヘッジホッグシグナルの受容体Ptch1は、奇形と高発癌性の基底細胞母斑症候群（ゴーリン症候群）の原因遺伝子である。本研究は、奇形発症の機序を理解する助けとなるだけでなく、Ptch1機能欠失による発癌の抑制を行える可能性を示した。

Research Products

• [Journal Article] ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H(+)-ATPases is essential for brain development in humans and mice (2021)
  • Author(s): Aoto K, Kato M, Akita T, Nakashima M, Mutoh H, Akasaka N, Tohyama J, Nomura Y, Hoshino K, Ago Y, Tanaka R, Epstein O, Ben-Haim R, Heyman E, Miyazaki T, Belal H, Takabayashi S, Ohba C, Takata A, Mizuguchi T, Miyatake S, Miyake N, Fukuda A, Matsumoto N and Saitsu H
  • Journal Title: Nat Commun Volume: 12 Issue: 1 Pages: 2107-2107
  • DOI: 10.1038/s41467-021-22389-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Parthenogenetic mosaicism: generation via second polar body retention and unmasking of a likely causative PER2 variant for hypersomnia (2021)
  • Author(s): Masunaga Yohei、Kagami Masayo、Kato Fumiko、Usui Takeshi、Yonemoto Takako、Mishima Kazuo、Fukami Maki、Aoto Kazushi、Saitsu Hirotomo、Ogata Tsutomu
  • Journal Title: Clinical Epigenetics Volume: 13 Issue: 1 Pages: 73-73
  • DOI: 10.1186/s13148-021-01062-0
  • NAID: 120007042184
  • Peer Reviewed / Open Access
• [Journal Article] Cell lineage‐ and expression‐based inference of the roles of forkhead box transcription factor Foxc2 in craniofacial development (2021)
  • Author(s): Takenoshita Manami、Takechi Masaki、Vu Hoang Tri、Furutera Toshiko、Akagawa Chisaki、Namangkalakul Worachat、Aoto Kazushi、Kume Tsutomu、Miyashin Michiyo、Iwamoto Tsutomu、Iseki Sachiko
  • Journal Title: Developmental Dynamics Volume: - Issue: 8 Pages: 1-10
  • DOI: 10.1002/dvdy.324
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nanopore sequencing reveals a structural alteration of mirror‐image duplicated genes in a genome‐editing mouse line (2019)
  • Author(s): Miyamoto Sachiko、Aoto Kazushi、Hiraide Takuya、Nakashima Mitsuko、Takabayashi Shuji、Saitsu Hirotomo
  • Journal Title: Congenital Anomalies Volume: - Issue: 4 Pages: 120-125
  • DOI: 10.1111/cga.12364
  • NAID: 210000157792
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] i-GONAD (improved genome-editing via oviductal nucleic acids delivery), a convenient in vivo tool to produce genome-edited rats (2018)
  • Author(s): Takabayashi Shuji、Aoshima Takuya、Kabashima Katsuya、Aoto Kazushi、Ohtsuka Masato、Sato Masahiro
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 12059-12059
  • DOI: 10.1038/s41598-018-30137-x
  • Peer Reviewed / Open Access
• [Journal Article] De novo variants in RHOBTB2, an atypical Rho GTPase gene, cause epileptic encephalopathy (2018)
  • Author(s): Belal Hazrat、Nakashima Mitsuko、Matsumoto Hiroshi、Yokochi Kenji、Taniguchi-Ikeda Mariko、Aoto Kazushi、Amin Mohammed Badrul、Maruyama Azusa、Nagase Hiroaki、Mizuguchi Takeshi、Miyatake Satoko、Miyake Noriko、Iijima Kazumoto、Nonoyama Shigeaki、Matsumoto Naomichi、Saitsu Hirotomo
  • Journal Title: Human Mutation Volume: 39 Issue: 8 Pages: 1070-1075
  • DOI: 10.1002/humu.23550
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy (2018)
  • Author(s): Nakashima Mitsuko、Kato Mitsuhiro、Aoto Kazushi、Shiina Masaaki、Belal Hazrat、Mukaida Souichi、Kumada Satoko、Sato Atsushi、Zerem Ayelet、Lerman-Sagie Tally、Lev Dorit、Leong Huey Yin、Tsurusaki Yoshinori、Mizuguchi Takeshi、Miyatake Satoko、Miyake Noriko、Ogata Kazuhiro、Saitsu Hirotomo、Matsumoto Naomichi
  • Journal Title: Annals of Neurology Volume: 83 Issue: 4 Pages: 794-806
  • DOI: 10.1002/ana.25208
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biallelic Variants in CNPY3 , Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset Epileptic Encephalopathy (2018)
  • Author(s): Mutoh Hiroki、Kato Mitsuhiro、Akita Tenpei、Shibata Takuma、Wakamoto Hiroyuki、Ikeda Hiroko、Kitaura Hiroki、Aoto Kazushi、Nakashima Mitsuko、Wang Tianying、Ohba Chihiro、Miyatake Satoko、Miyake Noriko、Kakita Akiyoshi、Miyake Kensuke、Fukuda Atsuo、Matsumoto Naomichi、Saitsu Hirotomo
  • Journal Title: The American Journal of Human Genetics Volume: 102 Issue: 2 Pages: 321-329
  • DOI: 10.1016/j.ajhg.2018.01.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders (2018)
  • Author(s): Akita Tenpei、Aoto Kazushi、Kato Mitsuhiro、Shiina Masaaki、Mutoh Hiroki、Nakashima Mitsuko、Kuki Ichiro、Okazaki Shin、Magara Shinichi、Shiihara Takashi、Yokochi Kenji、Aiba Kaori、Tohyama Jun、Ohba Chihiro、Miyatake Satoko、Miyake Noriko、Ogata Kazuhiro、Fukuda Atsuo、Matsumoto Naomichi、Saitsu Hirotomo
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 5 Issue: 3 Pages: 280-296
  • DOI: 10.1002/acn3.528
  • Peer Reviewed / Open Access
• [Journal Article] De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism (2018)
  • Author(s): Hiraide Takuya、Nakashima Mitsuko、Yamoto Kaori、Fukuda Tokiko、Kato Mitsuhiro、Ikeda Hiroko、Sugie Yoko、Aoto Kazushi、Kaname Tadashi、Nakabayashi Kazuhiko、Ogata Tsutomu、Matsumoto Naomichi、Saitsu Hirotomo
  • Journal Title: Human Genetics Volume: 137 Issue: 1 Pages: 95-104
  • DOI: 10.1007/s00439-017-1863-y
  • Peer Reviewed / Open Access
• [Presentation] GONAD法を用いたゲノム編集スモールタグノックインマウス作製による脳・顔面発生の解析：標的特異抗体の不必要の方法 (2019)
  • Author(s): 青戸一司、高林秀次、宮嵜岳大、才津浩智
  • Organizer: 第61回歯科基礎医学会学術大会
• [Presentation] GONAD法を用いたスモールタグノックインマウスの作製とその応用 (2019)
  • Author(s): 青戸一司、高林秀次、宮嵜岳大、才津浩智
  • Organizer: 第４回ゲノム編集学会