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

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.

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

2020 ◽  
Author(s):  
Satoshi Miyashita ◽  
Tomoo Owa ◽  
Yusuke Seto ◽  
Mariko Yamashita ◽  
Shogo Aida ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Granule Cell ◽  
Developmental Stages ◽  
Regulatory Mechanism ◽  
Histone Deacetylation ◽  
Cerebellar Granule Cell ◽  
Cell Cycle Exit ◽  
Cerebellar Granule ◽  
Prox1 Expression ◽  
Essential Transcription Factor

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.

scholarly journals ASCL1 drives induction of a transitory cell state required for repair of the injured neonatal brain

2020 ◽  
Author(s):  
N. Sumru Bayin ◽  
Dogukan Mizrak ◽  
Daniel N. Stephen ◽  
Zhimin Lao ◽  
Peter A. Sims ◽  
...  
Keyword(s):  
Transcription Factor ◽  
White Matter ◽  
Granule Cell ◽  
Molecular Subtypes ◽  
Cerebellar Granule Cell ◽  
Neonatal Brain ◽  
Regenerative Capacity ◽  
Cerebellar Granule ◽  
Granule Neuron

SummaryThe underlying molecular foundation of neural progenitor diversity and plasticity is critical for understanding repair processes. The neonatal cerebellum with multiple progenitor populations has high regenerative potential. Upon ablation of cerebellar granule cell progenitors at birth, a normally gliogenic Nestin-expressing progenitor (NEP) in the Bergmann glia (Bg) layer (BgL-NEPs) undergoes adaptive reprograming to restore granule neuron production while a white matter NEP (WM-NEPs) reduces interneuron production. However, the cellular states and genes regulating the NEP fate switch are not known. Here using scRNA-seq and fate-mapping, we defined the molecular subtypes of NEPs and their lineages under homeostasis and repair. Five NEP populations comprising two molecular subtypes, Hopx-expressing gliogenic- and Ascl1-expressing neurogenic-NEPs were identified in both states. Furthermore, in the WM, distinct NEP populations generate interneurons or astrocytes, and amongst gliogenic-NEPs, astrocyte and Bg lineages are molecularly separable. Importantly, we uncovered that after injury a new transitory cellular state arises from Hopx-NEPs in the BgL that is defined by initiation of expression of the neurogenic gene Ascl1. Moreover, Ascl1 is required for adaptive reprogramming and the full regenerative capacity of the cerebellum. We thus define new populations of NEPs and identifed the transcription factor responsible for inducing a transitory cell critical for a glial to neural switch in vivo following injury.

2-Halopropionic Acid-induced Cerebellar Granule Cell Necrosis in the Rat: In Vivo and In Vitro Studies

2001 ◽  
Vol 22 (3) ◽  
pp. 363-374 ◽  
Author(s):  
Edward A Lock ◽  
Andrew Gyte ◽  
Nicholas C Sturgess ◽  
Stephen Duffell ◽  
Ian Wyatt
Keyword(s):  
Granule Cell ◽  
Cerebellar Granule Cell ◽  
In Vitro Studies ◽  
Cell Necrosis ◽  
Cerebellar Granule ◽  
Cerebellar Granule Cell Necrosis

Nicotine modulates the facial stimulation-evoked responses in cerebellar granule cell layer in vivo in mice

2019 ◽  
Vol 843 ◽  
pp. 126-133
Author(s):  
Yin-Hua Xu ◽  
Bin-Bin Zhang ◽  
Wen-Hao Su ◽  
Mao-Cheng Wu ◽  
Yan-Hua Bing ◽  
...  
Keyword(s):  
Granule Cell ◽  
Cell Layer ◽  
Cerebellar Granule Cell ◽  
Granule Cell Layer ◽  
Evoked Responses ◽  
Cerebellar Granule

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

eLife ◽  
2016 ◽  
Vol 5 ◽  
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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