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Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis

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 th...

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Autores principales: Penas, Clara, Maloof, Marie E., Stathias, Vasileios, Long, Jun, Tan, Sze Kiat, Mier, Jose, Fang, Yin, Valdes, Camilo, Rodriguez-Blanco, Jezabel, Chiang, Cheng-Ming, Robbins, David J., Liebl, Daniel J., Lee, Jae K., Hatten, Mary E., Clarke, Jennifer, Ayad, Nagi G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620341/
https://www.ncbi.nlm.nih.gov/pubmed/31292434
http://dx.doi.org/10.1038/s41467-019-10799-5
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author Penas, Clara
Maloof, Marie E.
Stathias, Vasileios
Long, Jun
Tan, Sze Kiat
Mier, Jose
Fang, Yin
Valdes, Camilo
Rodriguez-Blanco, Jezabel
Chiang, Cheng-Ming
Robbins, David J.
Liebl, Daniel J.
Lee, Jae K.
Hatten, Mary E.
Clarke, Jennifer
Ayad, Nagi G.
author_facet Penas, Clara
Maloof, Marie E.
Stathias, Vasileios
Long, Jun
Tan, Sze Kiat
Mier, Jose
Fang, Yin
Valdes, Camilo
Rodriguez-Blanco, Jezabel
Chiang, Cheng-Ming
Robbins, David J.
Liebl, Daniel J.
Lee, Jae K.
Hatten, Mary E.
Clarke, Jennifer
Ayad, Nagi G.
author_sort Penas, Clara
collection PubMed
description 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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spelling pubmed-66203412019-07-15 Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis Penas, Clara Maloof, Marie E. Stathias, Vasileios Long, Jun Tan, Sze Kiat Mier, Jose Fang, Yin Valdes, Camilo Rodriguez-Blanco, Jezabel Chiang, Cheng-Ming Robbins, David J. Liebl, Daniel J. Lee, Jae K. Hatten, Mary E. Clarke, Jennifer Ayad, Nagi G. Nat Commun Article 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. Nature Publishing Group UK 2019-07-10 /pmc/articles/PMC6620341/ /pubmed/31292434 http://dx.doi.org/10.1038/s41467-019-10799-5 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Penas, Clara
Maloof, Marie E.
Stathias, Vasileios
Long, Jun
Tan, Sze Kiat
Mier, Jose
Fang, Yin
Valdes, Camilo
Rodriguez-Blanco, Jezabel
Chiang, Cheng-Ming
Robbins, David J.
Liebl, Daniel J.
Lee, Jae K.
Hatten, Mary E.
Clarke, Jennifer
Ayad, Nagi G.
Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis
title Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis
title_full Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis
title_fullStr Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis
title_full_unstemmed Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis
title_short Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis
title_sort time series modeling of cell cycle exit identifies brd4 dependent regulation of cerebellar neurogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620341/
https://www.ncbi.nlm.nih.gov/pubmed/31292434
http://dx.doi.org/10.1038/s41467-019-10799-5
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