論文

国際誌
2021年5月31日

Cyclin D1 controls development of cerebellar granule cell progenitors through phosphorylation and stabilization of ATOH1

The EMBO Journal
  • Satoshi Miyashita
  • ,
  • Tomoo Owa
  • ,
  • Yusuke Seto
  • ,
  • Mariko Yamashita
  • ,
  • Shogo Aida
  • ,
  • Masaki Sone
  • ,
  • Kentaro Ichijo
  • ,
  • Tomoki Nishioka
  • ,
  • Kozo Kaibuchi
  • ,
  • Yoshiya Kawaguchi
  • ,
  • Shinichiro Taya
  • ,
  • Mikio Hoshino

開始ページ
e105712
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.15252/embj.2020105712
出版者・発行元
EMBO

During development, neural progenitors are in proliferative and immature states; however, the molecular machinery that cooperatively controls both states remains elusive. Here, we report that cyclin D1 (CCND1) directly regulates both proliferative and immature states of cerebellar granule cell progenitors (GCPs). CCND1 not only accelerates cell cycle but also upregulates ATOH1 protein, an essential transcription factor that maintains GCPs in an immature state. In cooperation with CDK4, CCND1 directly phosphorylates S309 of ATOH1, which inhibits additional phosphorylation at S328 and consequently prevents S328 phosphorylation-dependent ATOH1 degradation. Additionally, PROX1 downregulates Ccnd1 expression by histone deacetylation of Ccnd1 promoter in GCPs, leading to cell cycle exit and differentiation. Moreover, WNT signaling upregulates PROX1 expression in GCPs. These findings suggest that WNT-PROX1-CCND1-ATOH1 signaling cascade cooperatively controls proliferative and immature states of GCPs. We revealed that the expression and phosphorylation levels of these molecules dynamically change during cerebellar development, which are suggested to determine appropriate differentiation rates from GCPs to GCs at distinct developmental stages. This study contributes to understanding the regulatory mechanism of GCPs as well as neural progenitors.

リンク情報
DOI
https://doi.org/10.15252/embj.2020105712
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/34057742
URL
https://onlinelibrary.wiley.com/doi/pdf/10.15252/embj.2020105712
URL
https://onlinelibrary.wiley.com/doi/full-xml/10.15252/embj.2020105712
ID情報
  • DOI : 10.15252/embj.2020105712
  • ISSN : 0261-4189
  • eISSN : 1460-2075
  • PubMed ID : 34057742

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