A Unilateral Negative Feedback Loop Between miR-200 microRNAs and Sox2/E2F3 Controls Neural Progenitor Cell-Cycle Exit and Differentiation

ABSTRACT Mechanisms coordinating neural progenitor cell cycle exit and differentiation are incompletely understood. The cyclin-dependent kinase inhibitor p27Kip1 is transcriptionally induced, switching specific neural progenitors from proliferation to differentiation. However, neuronal differentiation-specific transcription factors mediating p27Kip1 transcription have not been identified. We demonstrate the homeodomain transcription factor Phox2a, required for central nervous system (CNS)- and neural crest (NC)-derived noradrenergic neuron differentiation, coordinates cell cycle exit and differentiation by inducing p27Kip1 transcription. Phox2a transcription and activation in the CNS-derived CAD cell line and primary NC cells is mediated by combined cyclic AMP (cAMP) and bone morphogenetic protein 2 (BMP2) signaling. In the CAD cellular model, cAMP and BMP2 signaling initially induces proliferation of the undifferentiated precursors, followed by p27Kip1 transcription, G1 arrest, and neuronal differentiation. Small interfering RNA silencing of either Phox2a or p27Kip1 suppresses p27Kip1 transcription and neuronal differentiation, suggesting a causal link between p27Kip1 expression and differentiation. Conversely, ectopic Phox2a expression via the Tet-off expression system promotes accelerated CAD cell neuronal differentiation and p27Kip1 transcription only in the presence of cAMP signaling. Importantly, endogenous or ectopically expressed Phox2a activated by cAMP signaling binds homeodomain cis-acting elements of the p27Kip1 promoter in vivo and mediates p27Kip1-luciferase expression in CAD and NC cells. We conclude that developmental cues of cAMP signaling causally link Phox2a activation with p27Kip1 transcription, thereby coordinating neural progenitor cell cycle exit and differentiation.

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Histone chaperone HIRA regulates neural progenitor cell proliferation and neurogenesis via β-catenin

The Journal of Cell Biology ◽

10.1083/jcb.201610014 ◽

2017 ◽

Vol 216 (7) ◽

pp. 1975-1992 ◽

Cited By ~ 14

Author(s):

Yanxin Li ◽

Jianwei Jiao

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Progenitor Cell ◽

Neural Progenitor Cells ◽

Neural Progenitor Cell ◽

Neural Progenitor ◽

Histone Chaperone ◽

Epigenetic Mechanism ◽

Progenitor Cell Proliferation ◽

Early Neurogenesis

Histone cell cycle regulator (HIRA) is a histone chaperone and has been identified as an epigenetic regulator. Subsequent studies have provided evidence that HIRA plays key roles in embryonic development, but its function during early neurogenesis remains unknown. Here, we demonstrate that HIRA is enriched in neural progenitor cells, and HIRA knockdown reduces neural progenitor cell proliferation, increases terminal mitosis and cell cycle exit, and ultimately results in premature neuronal differentiation. Additionally, we demonstrate that HIRA enhances β-catenin expression by recruiting H3K4 trimethyltransferase Setd1A, which increases H3K4me3 levels and heightens the promoter activity of β-catenin. Significantly, overexpression of HIRA, HIRA N-terminal domain, or β-catenin can override neurogenesis abnormities caused by HIRA defects. Collectively, these data implicate that HIRA, cooperating with Setd1A, modulates β-catenin expression and then regulates neurogenesis. This finding represents a novel epigenetic mechanism underlying the histone code and has profound and lasting implications for diseases and neurobiology.

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Progesterone Increases Rat Neural Progenitor Cell Cycle Gene Expression and Proliferation Via Extracellularly Regulated Kinase and Progesterone Receptor Membrane Components 1 and 2

Endocrinology ◽

10.1210/en.2008-1447 ◽

2009 ◽

Vol 150 (7) ◽

pp. 3186-3196 ◽

Cited By ~ 62

Author(s):

Lifei Liu ◽

Junming Wang ◽

Liqin Zhao ◽

Jon Nilsen ◽

Kelsey McClure ◽

...

Keyword(s):

Cell Cycle ◽

Progesterone Receptor ◽

Progenitor Cell ◽

Neural Progenitor Cell ◽

Neural Progenitor ◽

Mammalian Brain ◽

Cell Cycle Gene ◽

Cell Cycle Genes ◽

Expression Of Genes ◽

Membrane Components

Progesterone receptor (PR) expression and regulation of neural progenitor cell (NPC) proliferation was investigated using NPC derived from adult rat brain. RT-PCR revealed that PRA mRNA was not detected in rat NPCs, whereas membrane-associated PRs, PR membrane components (PGRMCs) 1 and 2, mRNA were expressed. Progesterone-induced increase in 5-bromo-2-deoxyuridine incorporation was confirmed by fluorescent-activated cell sorting analysis, which indicated that progesterone promoted rat NPC exit of G0/G1 phase at 5 h, followed by an increase in S-phase at 6 h and M-phase at 8 h, respectively. Microarray analysis of cell-cycle genes, real-time PCR, and Western blot validation revealed that progesterone increased expression of genes that promote mitosis and decreased expression of genes that repress cell proliferation. Progesterone-induced proliferation was not dependent on conversion to metabolites and was antagonized by the ERK1/2 inhibitor UO126. Progesterone-induced proliferation was isomer and steroid specific. PGRMC1 small interfering RNA treatment, together with computational structural analysis of progesterone and its isomers, indicated that the proliferative effect of progesterone is mediated by PGRMC1/2. Progesterone mediated NPC proliferation and concomitant regulation of mitotic cell cycle genes via a PGRMC/ERK pathway mechanism is a potential novel therapeutic target for promoting neurogenesis in the mammalian brain.

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Erythropoietin promotes spinal cord-derived neural progenitor cell proliferation by regulating cell cycle

Neuroscience ◽

10.1016/j.neuroscience.2010.02.007 ◽

2010 ◽

Vol 167 (3) ◽

pp. 750-757 ◽

Cited By ~ 12

Author(s):

Y. Wang ◽

M. Yao ◽

C. Zhou ◽

D. Dong ◽

Y. Jiang ◽

...

Keyword(s):

Cell Cycle ◽

Spinal Cord ◽

Cell Proliferation ◽

Progenitor Cell ◽

Neural Progenitor Cell ◽

Neural Progenitor ◽

Progenitor Cell Proliferation

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The mTOR pathway component Unkempt regulates neural stem cell and neural progenitor cell cycle in the Drosophila central nervous system

Developmental Biology ◽

10.1016/j.ydbio.2020.01.006 ◽

2020 ◽

Vol 461 (1) ◽

pp. 55-65

Author(s):

Katja T. Maierbrugger ◽

Rita Sousa-Nunes ◽

Joseph M. Bateman

Keyword(s):

Cell Cycle ◽

Central Nervous System ◽

Nervous System ◽

Stem Cell ◽

Neural Stem Cell ◽

Progenitor Cell ◽

Neural Progenitor Cell ◽

Neural Progenitor ◽

Mtor Pathway

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Zika Virus Overview: Transmission, Origin, Pathogenesis, Animal Model and Diagnosis

Zoonoses ◽

10.15212/zoonoses-2021-0017 ◽

2021 ◽

Vol 1 (1) ◽

Author(s):

Dallas Vue ◽

Qiyi Tang

Keyword(s):

Cell Cycle ◽

Zika Virus ◽

Progenitor Cell ◽

Olympic Games ◽

Neural Progenitor Cell ◽

Neural Progenitor ◽

Review Article ◽

Zikv Infection ◽

Cycle Arrest ◽

Mitotic Abnormalities

Zika virus (ZIKV) was first discovered in 1947 in Uganda. ZIKV did not receive substantial attention until Brazil hosted the 2016 Summer Olympic Games, and ZIKV reached a global audience. ZIKV is a flavivirus transmitted chiefly through mosquito bites, sexual intercourse and, to a lesser extent, breastfeeding. The recent discovery of how ZIKV causes congenital neurodevelopmental defects, including microcephaly, has led to reevaluation of the importance of the interaction of ZIKV with centrosome organization, because centrosomes play an important role in cell division. When ZIKV disrupts centrosome organization and mitotic abnormalities, neural progenitor differentiation is altered, thereby resulting in cell cycle arrest, increased apoptosis and inhibition of neural progenitor cell differentiation; subsequently, abnormalities in neural cell development can result in microcephaly. To aid in the understanding of the importance of ZIKV infection, this review article provides an overview of its history, transmission routes, pathogenesis, animal models and diagnosis.

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