Molecular mechanisms underlying acquisition and maintenance of cerebral cortical progenitor identity by Dmrt factors

• Project/Area Number: 15K06727
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurophysiology / General neuroscience
• Research Institution: Kyushu University (2018); Institute of Physical and Chemical Research (2015-2017)
• Principal Investigator: Konno Daijiro 九州大学, 生体防御医学研究所, 准教授 (00362715)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 神経前駆細胞 / 大脳皮質 / 神経幹細胞

Outline of Final Research Achievements

The spatio-temporal identity of neural progenitors and the regional control of neurogenesis are essential for the development of cerebral cortical architecture. This research project revealed a novel transcriptional network in which mammalian DM-domain containing transcription factors (Dmrts) confer the identity of the cerebral cortical progenitors by providing the positional information via dose-dependent suppression of developmental patterning factors including Gsx2 and pax6. Our results indicate that differential suppression of Gsx2 and Pax6 expression by Dmrt factors is a key mechanism not only for acquiring the cerebral cortical identity of progenitors but also for regulation of brain region size by negatively regulating neurogenesis. Thus, our findings provide new insights into the long-standing question of how vertebrate species acquired the cerebral cortex and how it enlarged in mammals during evolution.

Academic Significance and Societal Importance of the Research Achievements

個体発生において多分化能を持つ胚性幹細胞からより運命の限定された体性幹細胞・前駆細胞に分化する過程の分子的理解は、発生現象を制御する分子機構の解明だけでなく、体性幹細胞を用いた再生医療の実現においても重要な意味を持つ。本研究では、胎生期大脳皮質神経前駆細胞の個性獲得・維持に必須の分子メカニズムを明らかにし、神経幹細胞・前駆細胞を用いた再生医療の実現に向けて新たな知見を提供する画期的な成果となった。

Research Products

• [Int'l Joint Research] CNRS(France)
• [Int'l Joint Research] European Institute of Oncology(Italy)
• [Journal Article] Loss of the canonical spindle orientation function in the Pins/LGN homolog AGS3 (2017)
  • Author(s): Saadaoui Mehdi、Konno Daijiro、Loulier Karine、Goiame Rosette、Jadhav Vaibhav、Mapelli Marina、Matsuzaki Fumio、Morin Xavier
  • Journal Title: EMBO reports Volume: 18 Issue: 9 Pages: 1509-1520
  • DOI: 10.15252/embr.201643048
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prdm16 is crucial for progression of the multipolar phase during neural differentiation of the developing neocortex. (2017)
  • Author(s): Inoue M, Iwai R, Tabata H, Konno D, Komabayashi-Suzuki M, Watanabe C, Iwanari H, Mochizuki Y, Hamakubo T, Matsuzaki F, Nagata K-I, Mizutani K-I
  • Journal Title: Development Volume: 144 Issue: 3 Pages: 385-399
  • DOI: 10.1242/dev.136382
  • Peer Reviewed
• [Journal Article] Cell-cycle-independent transitions in temporal identity of mammalian neural progenitor cells (2016)
  • Author(s): Okamoto M, Miyata T, Konno D, Ueda HR, Kasukawa T, Hashimoto M, Matsuzaki F, Kawaguchi A
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 11349-11349
  • DOI: 10.1038/ncomms11349
  • Peer Reviewed / Open Access
• [Journal Article] Prox1 Inhibits Proliferation and Is Required for Differentiation of the Oligodendrocyte Cell Lineage in the Mouse (2015)
  • Author(s): Kato K, Konno D, Berry M, Matsuzaki F, Logan A, Hidalgo A
  • Journal Title: PLoS One Volume: 10 Issue: 12 Pages: e0145334-e0145334
  • DOI: 10.1371/journal.pone.0145334
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] STAP cells are derived from ES cells (2015)
  • Author(s): Konno D, Kasukawa T, Hashimoto K, Itoh T, Suetsugu T, Miura I, Wakana S, Carninci P, Matsuzaki F
  • Journal Title: Nature Volume: 525 Issue: 7570 Pages: E4-E5
  • DOI: 10.1038/nature15366
  • Peer Reviewed / Open Access
• [Journal Article] Impairment of radial glial scaffold-dependent neuronal migration and formation of double cortex by genetic ablation of afadin. (2015)
  • Author(s): Yamamoto H, Mandai K, Konno D, Maruo T, Matsuzaki F, Takai Y
  • Journal Title: Brain Res Volume: 43 Pages: 775-86
  • DOI: 10.1016/j.brainres.2015.05.012
  • Peer Reviewed
• [Presentation] Dmrt transcription factors orchestrate the cerebral cortical development via integrating positional information in neural progenitors (2018)
  • Author(s): Dai-jiro KONNO and Fumio MATSUZAKI
  • Organizer: 22nd Biennial MeeCng of the InternaConal Society of Developmental Neuroscience
  • Int'l Joint Research