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Cyclin D1 controls development of cerebellar granule cell progenitors through phosphorylation and stabilization of ATOH1
Author(s) -
Miyashita Satoshi,
Owa Tomoo,
Seto Yusuke,
Yamashita Mariko,
Aida Shogo,
Sone Masaki,
Ichijo Kentaro,
Nishioka Tomoki,
Kaibuchi Kozo,
Kawaguchi Yoshiya,
Taya Shinichiro,
Hoshino Mikio
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020105712
Subject(s) - biology , wnt signaling pathway , phosphorylation , progenitor cell , microbiology and biotechnology , cyclin d1 , transcription factor , progenitor , cell cycle , granule cell , cancer research , signal transduction , stem cell , cell , genetics , gene , neuroscience , hippocampal formation , dentate gyrus
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.