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

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. SYNOPSIS: CCND1‐dependent phosphorylation and stabilization of ATOH1 in granule progenitor cells is dynamically regulated by the WNT‐PROX1 pathway during cerebellar development and determines the rate of granule cell (GC) differentiation from granule cell progenitors (GCPs). The expression of ATOH1 and NEUROD1 distinguishes two different progenitor maturation stages in the developing cerebellar external granule cell layer.CCND1/CDK4‐mediated phosphorylation of ATOH1 at Ser309 prevents its phosphorylation at Ser328 and thereby ATOH1 degradation.Increased expression of WNT and PROX1 promotes differentiation of GCPs to GCs by suppressing the expression of CCND1. [ABSTRACT FROM AUTHOR]