Comprehensive analysis to identify genes involved in the production of outer subventricular zone progenitors

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06893
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46020:Anatomy and histopathology of nervous system-related
• Research Institution: Yokohama City University
• Principal Investigator: HIROSE Tomonori 横浜市立大学, 医学部, 講師 (20381668)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: PAR3 (PARD3) / 神経産生 / 終脳 / ヘッジホッグ系 / 一次線毛 / ノックアウトマウス

Outline of Final Research Achievements

During brain development, neural precursor cells (NPCs) expand initially, and then switch to generating stage-specific neurons while maintaining self-renewal ability. However, the molecular mechanisms underlying this transition are poorly
understood. In this study, we found that the telencephalon-specific loss of PAR3 before the start of neurogenesis leads to increased NPC proliferation at the expense of neurogenesis. These NPCs demonstrate hyperactivation of hedgehog signaling in a smoothened-dependent manner, as well as defects in primary cilia. Furthermore, loss of PAR3 enhanced ligand-independent ciliary accumulation of smoothened and an inhibitor of smoothened ameliorated the hyperproliferation of NPCs in the telencephalon. Thus, these findings support the idea that PAR3 has a crucial role in the transition of NPCs from the expansion phase to the neurogenic phase by restricting hedgehog signaling through the establishment of ciliary integrity.

Free Research Field

神経発生

Academic Significance and Societal Importance of the Research Achievements

神経幹細胞・前駆細胞が増幅期から神経産生期に移行するタイミングの制御は、最終的な神経細胞数を規定することになるため、大脳形成にとって極めて重要な局面である。しかし、この制御に関わる分子機構はほとんど理解が進んでいなかった。本研究によって、この制御機構では細胞極性制御因子PAR3によるヘッジホッグ系の制限が重要な働きを持つことを明らかにした。更に、高等哺乳類の大脳皮質形成に寄与していると考えられている脳室帯外神経幹細胞（OSVZCs）を含む神経産生機構において、ヘッジホッグ系の制限解除が寄与している可能性が示唆された。