Neuronal specification and differentiation in the cerebellum

2018 Fiscal Year Final Research Report

• Project/Area Number: 15H04268
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: Hoshino Mikio 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 病態生化学研究部, 部長 (70301273)
• Research Collaborator: OWA tomoo ; MIYASHITA satoshi
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 小脳 / 転写因子 / 発生

Outline of Final Research Achievements

Cerebellar granule cell precursors (GCPs) and granule cells (GCs) represent good models to study neuronal development. We found that Meis1 is expressed in granule cell lineage cells and astrocytes in the cerebellum during development. Targeted disruption of the Meis1 gene specifically in the GC lineage resulted in smaller cerebella with disorganized lobules. Knockdown/knockout experiments for Meis1 as well as in vitro assays show that Meis1 binds to an upstream sequence of Pax6 to enhance its transcription in GCPs/GCs. Furthermore, we found that the Meis1-Pax6 pathway increases the expression of Smad proteins to upregulate BMP signaling, leading to degradation of Atoh1 in the inner EGL, which contributes to differentiation from GCPs to GCs. Thus, this work reveals multiple functions of Meis1 in GC development and gives insights into the general understanding of the molecular machinery underlying neural differentiation from neural progenitors.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

今回の知見により、これまで個別に明らかにされてきた小脳顆粒細胞の発生の分子機構を、MEIS1というハブによって統合的に理解することが可能となった。これは小脳にとどまらず、様々な脳部位での神経前駆細胞から神経細胞が生み出されるしくみの理解につながると考えられる。また、MEIS1は一部の髄芽腫において異常に強く発現しており、髄芽腫の発症に関与している可能性も考えられるために、今回の研究成果は広く今後の小脳癌研究の発展に寄与すると考えられる。