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

Clara Penas; Marie E Maloof; Vasileios Stathias; Jun Long; Sze Kiat Tan; Jose Mier; Yin Fang; Camilo Valdes; Jezabel Rodriguez-Blanco; Cheng-Ming Chiang; David J Robbins; Daniel J Liebl; Jae K Lee; Mary E Hatten; Jennifer Clarke; Nagi G Ayad

doi:10.1038/s41467-019-10799-5

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

Journal article

Open access

Peer reviewed

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

Clara Penas, Marie E Maloof, Vasileios Stathias, Jun Long, Sze Kiat Tan, Jose Mier, Yin Fang, Camilo Valdes, Jezabel Rodriguez-Blanco, Cheng-Ming Chiang, …

Nature communications, Vol.10(1), pp.3028-11

2019-07-10

DOI: https://doi.org/10.1038/s41467-019-10799-5

PMCID: PMC6620341

PMID: 31292434

Abstract

Phosphorylation - physiology

Zinc Finger Protein GLI1 - metabolism

Cerebellar Cortex - growth & development

Humans

Neurons - physiology

Nuclear Proteins - genetics

Cell Differentiation - physiology

Disease Models, Animal

Animals, Newborn

Casein Kinase Idelta

Cerebellar Cortex - cytology

Down-Regulation

Cell Proliferation - physiology

Neural Stem Cells - physiology

Nuclear Proteins - metabolism

Cerebellar Ataxia - pathology

Transcription Factors - genetics

Mice, Knockout

Transcription Factors - metabolism

Animals

Cerebellar Ataxia - genetics

Cerebellar Cortex - pathology

Neurogenesis - physiology

Cell Cycle - physiology

Mice

Primary Cell Culture

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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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.54 Molecular & Cell Biology - Genetics; 1.54.2447 Bromodomains
Web Of Science research areas: Cell Biology
ESI research areas: Molecular Biology & Genetics

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Title: Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis
Creators: Clara Penas - Institut de Neurociències, Departament de Biologia Cellular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, CIBERNED, Bellaterra, 08193, Spain
Marie E Maloof - Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, Sylvester Comprehensive Cancer Center, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Vasileios Stathias - Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, Sylvester Comprehensive Cancer Center, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Jun Long - Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Sze Kiat Tan - Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, Sylvester Comprehensive Cancer Center, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Jose Mier - Department of Neurosurgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Yin Fang - Laboratory of Development Neurobiology, The Rockefeller University, New York, NY, 10065, USA
Camilo Valdes - Computing and Information Sciences, Florida International University, Miami, FL, 33199, USA
Jezabel Rodriguez-Blanco - Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Cheng-Ming Chiang - Simmons Comprehensive Cancer Center, Department of Biochemistry and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
David J Robbins - Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Daniel J Liebl - Department of Neurosurgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Jae K Lee - Department of Neurosurgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Mary E Hatten - Laboratory of Development Neurobiology, The Rockefeller University, New York, NY, 10065, USA
Jennifer Clarke - Department of Statistics, University of Nebraska, Lincoln, NE, 68588, USA
Nagi G Ayad - Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, Sylvester Comprehensive Cancer Center, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. nayad@miami.edu
Publication Details: Nature communications, Vol.10(1), pp.3028-11
Publisher: England
Grant note: R01 CA103867 / NCI NIH HHS R01 NS067289 / NINDS NIH HHS R56 NS102590 / NINDS NIH HHS
Academic Unit: Miller School of Medicine; Miami Project to Cure Paralysis; UMMG Department of Surgery; UMMG Dept of Neurological Surgery; UMMG Dept of Psychiatry & Behavioral Sciences; UMMG Dept of Surgery - Div of Surgical Oncology
Language: English
Resource Type: Journal article
PMID: 31292434
PMCID: PMC6620341
Record Identifier: 991031576807202976