pathophysiology of DUSP22 and MTNR1 gene abnormalities

• Project/Area Number: 17K16294
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Institute for Developmental Research Aichi Developmental Disability Center
• Principal Investigator: HAMADA NANAKO 愛知県医療療育総合センター発達障害研究所, 分子病態研究部, 研究員 (70721835)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 自閉スペクトラム症 / ASD / Dusp22 / MRTNR / DUSP22 / 自閉症 / 大脳皮質形成

Outline of Final Research Achievements

We examined the role of MTNR1A, 1B and DUSP22 in brain development and the pathophysiological significance of these gene abnormalities. Information of tissue and subcellular distribution of Dusp22 is largely unknown while information on the quality of commercially available antibodies is very limited. Therefore, we here produced a rabbit polyclonal antibody specific for Dusp22 and performed expression analyses of the molecule. While western blotting analyses clarified that Dusp22 was dominantly expressed in heart and skeletal muscle. Dusp22 was diffusely distributed in the cytoplasm and partially colocalized with actin cytoskeleton. Silencing of DUSP22 prevented dendrite development in cortical pyramidal cells in vivo. Knockdown of MTNR1A and 1B did not affected cell morphology.

Academic Significance and Societal Importance of the Research Achievements

これまで全く不明であった自閉症関連遺伝子DUSP22のマウス発達期の組織ごとの発現や細胞内局在について詳細に示すことができた。

Research Products

• [Journal Article] Heterotrimeric G-protein, Gi1, is involved in the regulation of proliferation, neuronal migration and dendrite morphology during cortical development in vivo. (2021)
  • Author(s): Hamada N, Iwamoto I, Kawamura N, Nagata K.
  • Journal Title: J. Neurochem. Volume: 1 Issue: 4 Pages: 1-1
  • DOI: 10.1111/jnc.15205
  • Peer Reviewed
• [Journal Article] Pogz deficiency leads to transcription dysregulation and impaired cerebellar activity underlying autism-like behavior in mice. (2020)
  • Author(s): Reut Suliman-Lavie, Ben Title, Yahel Cohen, Hamada N, Maayan Tal, Nitzan Tal, Galya Monderer- Rothkoff, Bjorg Gudmundsdottir, Kristbjorn O Gudmundsson, Jonathan R Keller, Guo-Jen Huang, Nagata K, Yosef Yarom, Sagiv Shifman.
  • Journal Title: Nat. Commun. Volume: 11 Issue: 1 Pages: 5836-5836
  • DOI: 10.1038/s41467-020-19577-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuropathophysiological significance of the c.1449T>C/p.(Tyr64Cys) mutation in the CDC42 gene responsible for Takenouchi-Kosaki syndrome (2020)
  • Author(s): Hamada Nanako、Ito Hidenori、Shibukawa Yukinao、Morishita Rika、Iwamoto Ikuko、Okamoto Nobuhiko、Nagata Koh-ichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 529 Issue: 4 Pages: 1033-1037
  • DOI: 10.1016/j.bbrc.2020.06.104
  • Peer Reviewed
• [Journal Article] Expression analyses of POGZ, a responsible gene for neurodevelopmental disorders, during mouse brain development. (2019)
  • Author(s): Ibaraki K, Hamada N, Iwamoto I, Ito H, Kawamura N, Morishita R, Tabata H, Nagata KI.
  • Journal Title: Dev Neurosci. Volume: 41 Issue: 1-2 Pages: 139-148
  • DOI: 10.1159/000502128
  • Peer Reviewed
• [Journal Article] MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome. (2018)
  • Author(s): Kato K, Miya F, Hamada N, Negishi Y, Kishimoto N, Ozawa H, Ito H, Hori I, Hattori A, Okamoto N, Kato M, Tsunoda T, Kanemura Y, Kosaki K, Takahashi Y, Nagata K, Saitoh S.
  • Journal Title: J. Med. Genet Volume: 0 Pages: 1-8
  • Peer Reviewed
• [Journal Article] De novo PHACTR1 mutations in West Syndrome and their pathophysiological effects. (2018)
  • Author(s): Hamada N, Ogaya S, Nakashima M, Nishijo T, Sugawara Y, Iwamoto I, Ito H, Maki Y, Shirai K, Baba S, Maruyama K, Saitsu H, Kato M, Matsumoto M, Momiyama T, Nagata K
  • Journal Title: Brain Volume: 141 Pages: 3098-3114
  • Peer Reviewed
• [Journal Article] Expression analyses of Dusp22 (Dual-specificity phosphatase 22) in mouse tissues (2017)
  • Author(s): Hamada N, Mizuno M, Tomita H, Iwamoto I, Hara A, Nagata K
  • Journal Title: Med. Mol. Morphol. Volume: 418 Pages: 475-481
  • Peer Reviewed
• [Journal Article] MUNC18-1 gene abnormalities are involved in neurodevelopmental disorders through defective cortical architecture during brain development (2017)
  • Author(s): Hamada N, Iwamoto I, Tabata H, Nagata K.
  • Journal Title: Acta Neuropathologica Comm. Volume: 5
  • Peer Reviewed / Open Access
• [Presentation] 発達障害関連遺伝子GNAI1の神経発達における機能解明 (2021)
  • Author(s): 浜田奈々子、永田浩一
  • Organizer: 日本小児遺伝学会
• [Presentation] 三量体Gタンパク質Gi1の神経発達における形態学的機能解析 (2020)
  • Author(s): 浜田奈々子、永田浩一
  • Organizer: 日本臨床分子形態学会
• [Presentation] Role of a heterotrimeric G-protein, Gi1, in the corticogenesis. (2020)
  • Author(s): 浜田奈々子、永田浩一
  • Organizer: 日本神経化学会
• [Presentation] Role of a heterotrimeric G-protein, Gαi1, regulates neurogenesis, migration and development in cortical excitatory neurons. (2020)
  • Author(s): 浜田奈々子、永田浩一
  • Organizer: 日本神経科学大会
• [Presentation] De novo PHACTR1 mutations in West syndrome and their pathophysiological effects (2020)
  • Author(s): 浜田奈々子、大萱俊介、中島光子、西條琢磨、才津浩智、加藤光広、松本直通、籾山俊彦、永田浩一
  • Organizer: CIBoGリトリート
• [Presentation] De novo PHACTR1 mutations in West Syndrome and their pathophysiological effects. (2019)
  • Author(s): 浜田奈々子、大萱俊介、中島光子、西條琢磨、才津浩智、加藤光広、松本直通、籾山俊彦、永田浩一
  • Organizer: The 20th Annual Meeting of Infantile Seizure Society
  • Int'l Joint Research
• [Presentation] 大脳皮質神経細胞の樹状突起形成におけるGαi1の役割 (2019)
  • Author(s): 浜田奈々子、岩本郁子、河村則子、田畑秀典、永田浩一
  • Organizer: 日本神経科学会・日本神経化学会
• [Presentation] 小児難治性てんかん原因遺伝子の病態生理解析 (2019)
  • Author(s): 浜田奈々子、大萱俊介、牧 祐輝、丸山幸一、永田浩一
  • Organizer: 日本臨床分子形態学会
• [Presentation] ウエスト症候群の新規責任遺伝子の同定と病態機能解析 (2019)
  • Author(s): 浜田奈々子
  • Organizer: 小児遺伝学会
• [Presentation] De novo PHACTR1 mutations in West Syndrome and their pathophysiological effects. (2018)
  • Author(s): 永田浩一
  • Organizer: Society for neuroscience 2018
  • Int'l Joint Research
• [Presentation] Identification of PHACTR1 as a novel causal gene for West Syndrome and pathophysiological significance of the gene mutations (2018)
  • Author(s): 浜田奈々子
  • Organizer: 日本神経化学会
• [Presentation] 小児難治性てんかん責任遺伝子の病態生理解析 (2018)
  • Author(s): 浜田奈々子
  • Organizer: 生理学研究所研究会「神経発達・再生研究会」
• [Presentation] Munc18-1 plays an essential role for cortical neuron migration during brain development (2017)
  • Author(s): 浜田奈々子、田畑秀典、永田浩一
  • Organizer: 日本神経化学会
• [Presentation] Role of Munc18-1 in cortical neuron migration (2017)
  • Author(s): 浜田奈々子、田畑秀典、永田浩一
  • Organizer: 日本生化学会
• [Presentation] Role of MUNC18-1 in brain development and involvement in early infantile epilepsies (2017)
  • Author(s): Koh-Ichi Nagata and Nanako Hamada
  • Organizer: Excitatory Synapses & Brain Function
  • Int'l Joint Research
• [Presentation] Pathophysiological significance of early infantile epilepsies caused by MUNC18-1 mutations (2017)
  • Author(s): Koh-Ichi Nagata and Nanako Hamada
  • Organizer: 48th ASN Annual Meeting
  • Int'l Joint Research
• [Presentation] Pathophysiological mechanism of MUNC18-1 mutations in early infantile epilepsies (2017)
  • Author(s): Koh-Ichi Nagata and Nanako Hamada
  • Organizer: ISN-ESN Meeting
  • Int'l Joint Research
• [Remarks] 発達障害研究所分子病態研究部
  • URL: https://www.pref.aichi.jp/addc/eachfacility/hattatsu/department/index4.html
• [Remarks] 愛知県医療療育総合センター発達障害研究所
  • URL: https://www.pref.aichi.jp/addc/eachfacility/hattatsu/index.html
• [Remarks] 発達障害研究所神経制御学部の紹介
  • URL: http://www.inst-hsc.jp/d-molecular/index.html