Cyclin D1 controls development of cerebellar granule cell progenitors through phosphorylation and stabilization of ATOH1
| Autor: | Kozo Kaibuchi, Masaki Sone, Yoshiya Kawaguchi, Shinichiro Taya, Yusuke Seto, Kentaro Ichijo, Shogo Aida, Tomoo Owa, Tomoki Nishioka, Mariko Yamashita, Mikio Hoshino, Satoshi Miyashita |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
ATOH1
Neurogenesis Cytoplasmic Granules General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Cyclin D1 Cerebellum hemic and lymphatic diseases Basic Helix-Loop-Helix Transcription Factors medicine Animals Hedgehog Proteins Phosphorylation neoplasms Molecular Biology Transcription factor Cells Cultured Cell Proliferation 030304 developmental biology 0303 health sciences General Immunology and Microbiology biology Stem Cells General Neuroscience Cell Cycle Wnt signaling pathway Cell Differentiation Articles Cell cycle Granule cell Cell biology Histone medicine.anatomical_structure biology.protein Corrigendum Cell Division 030217 neurology & neurosurgery Signal Transduction Transcription Factors |
| Zdroj: | EMBO J |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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