CyclinD1 controls development of cerebellar granule cell progenitors through phosphorylation and stabilization of ATOH1

AbstractHere we report that CyclinD1 (CCND1) directly regulates both the 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 Ser309 of ATOH1, which inhibits additional phosphorylation at S328, consequently preventing Ser328 phosphorylation-dependent ATOH1 degradation. PROX1 downregulates Ccnd1 expression by histone-deacetylation of Ccnd1 promoter in GCPs, leading to cell cycle exit and differentiation. WNT signaling upregulates PROX1 expression in GCPs. These findings suggest that WNT-PROX1-CCND1-ATOH1 signaling cascade cooperatively controls proliferation and immaturity of GCPs. We revealed that the expression and phosphorylation levels of these molecules dynamically change during cerebellar development, which was 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.

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GENE-44. BRD4 DELETION LEADS TO CEREBELLAR DEFICITS AND ATAXIA

Neuro-Oncology ◽

10.1093/neuonc/noz175.446 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi107-vi107

Author(s):

Nagi Ayad

Keyword(s):

Cell Cycle ◽

Granule Cell ◽

Neurological Diseases ◽

Pediatric Brain Tumor ◽

Cerebellar Granule Cell ◽

Cell Cycle Exit ◽

Cell Cycle Time ◽

Cerebellar Granule ◽

Conditional Deletion

Abstract Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications.

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Restoration in vitro of the normal timing of exiting of cerebellar granule cell precursors from the cell cycle by Sonic hedgehog

Neuroscience Research ◽

10.1016/s0168-0102(00)81629-6 ◽

2000 ◽

Vol 38 ◽

pp. S130

Author(s):

Y Ishizaki

Keyword(s):

Cell Cycle ◽

Sonic Hedgehog ◽

Granule Cell ◽

Cerebellar Granule Cell ◽

Cerebellar Granule ◽

Granule Cell Precursors

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Cell Cycle Elongation Impairs Proliferation of Cerebellar Granule Cell Precursors in the Ts65Dn Mouse, an Animal Model for Down Syndrome

Brain Pathology ◽

10.1111/j.1750-3639.2008.00168.x ◽

2009 ◽

Vol 19 (2) ◽

pp. 224-237 ◽

Cited By ~ 41

Author(s):

Andrea Contestabile ◽

Tatiana Fila ◽

Renata Bartesaghi ◽

Elisabetta Ciani

Keyword(s):

Cell Cycle ◽

Animal Model ◽

Down Syndrome ◽

Granule Cell ◽

Cerebellar Granule Cell ◽

Ts65dn Mouse ◽

Cerebellar Granule ◽

Granule Cell Precursors

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Decision letter: Proneurotrophin-3 promotes cell cycle withdrawal of developing cerebellar granule cell progenitors via the p75 neurotrophin receptor

10.7554/elife.16654.024 ◽

2016 ◽

Keyword(s):

Cell Cycle ◽

Granule Cell ◽

Cerebellar Granule Cell ◽

Neurotrophin Receptor ◽

P75 Neurotrophin Receptor ◽

Cerebellar Granule

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Proneurotrophin-3 promotes cell cycle withdrawal of developing cerebellar granule cell progenitors via the p75 neurotrophin receptor

eLife ◽

10.7554/elife.16654 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 16

Author(s):

Juan Pablo Zanin ◽

Elizabeth Abercrombie ◽

Wilma J Friedman

Keyword(s):

Cell Cycle ◽

Granule Cell ◽

Death Receptor ◽

Cerebellar Granule Cell ◽

Neurotrophin Receptor ◽

Motor Deficits ◽

P75 Neurotrophin Receptor ◽

Cerebellar Granule ◽

Neuronal Progenitors ◽

Normal Period

Cerebellar granule cell progenitors (GCP) proliferate extensively in the external granule layer (EGL) of the developing cerebellum prior to differentiating and migrating. Mechanisms that regulate the appropriate timing of cell cycle withdrawal of these neuronal progenitors during brain development are not well defined. The p75 neurotrophin receptor (p75NTR) is highly expressed in the proliferating GCPs, but is downregulated once the cells leave the cell cycle. This receptor has primarily been characterized as a death receptor for its ability to induce neuronal apoptosis following injury. Here we demonstrate a novel function for p75NTR in regulating proper cell cycle exit of neuronal progenitors in the developing rat and mouse EGL, which is stimulated by proNT3. In the absence of p75NTR, GCPs continue to proliferate beyond their normal period, resulting in a larger cerebellum that persists into adulthood, with consequent motor deficits.

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