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Bi-modal reprogramming of cell cycle by MiRNA-4673 amplifies human neurogenic capacity.

ABSTRACT: Molecular mechanisms that inform heterochronic adaptations of neurogenesis in Homo sapiens remain largely unknown. Here, we uncover a signature in the cell cycle that amplifies the proliferative capacity of human neural progenitors by input from microRNA4673 encoded in Notch-1. The miRNA instructs bimodal reprogramming of the cell cycle, leading to initial synchronization of neural precursors at the G0 phase of the cell cycle followed by accelerated progression through interphase. The key event in G0 synchronization is transient inhibition by miR4673 of cyclin-dependent kinase-18, a member of an ancient family of cyclins that license M-G1 transition. In parallel, autophagic degradation of p53/p21 and transcriptional silencing of XRCC3/BRCA2 relax G1/S cell cycle checkpoint and accelerate interphase by ?2.8-fold. The resultant reprogrammed cell cycle amplifies the proliferative capacity and delays the differentiation of human neural progenitors.

SUBMITTER: Farahani R

PROVIDER: S-EPMC6527295 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Bi-modal reprogramming of cell cycle by MiRNA-4673 amplifies human neurogenic capacity.

Farahani Ramin R Rezaei-Lotfi Saba S Simonian Mary M Hunter Neil N

Cell cycle (Georgetown, Tex.) 20190414 8

Molecular mechanisms that inform heterochronic adaptations of neurogenesis in Homo sapiens remain largely unknown. Here, we uncover a signature in the cell cycle that amplifies the proliferative capacity of human neural progenitors by input from microRNA4673 encoded in Notch-1. The miRNA instructs bimodal reprogramming of the cell cycle, leading to initial synchronization of neural precursors at the G0 phase of the cell cycle followed by accelerated progression through interphase. The key event ...[more]

PMID: 30907228

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Project description:Many bacteria mediate important life-style decisions by varying levels of the second messenger c-di-GMP. Behavioral transitions result from the coordination of complex cellular processes such as motility, surface adherence or the production of virulence factors and toxins. While the regulatory mechanisms responsible for these processes have been elucidated in some cases, the global pleiotropic effects of c-di-GMP are poorly understood, primarily because c-di-GMP networks are inherently complex in most bacteria. Moreover, the quantitative relationships between cellular c-di-GMP levels and c-di-GMP dependent phenotypes are largely unknown. Here, we dissect the c-di-GMP network of Caulobacter crescentus to establish a global and quantitative view of c-di-GMP dependent processes in this organism. A genetic approach that gradually reduced the number of diguanylate cyclases identified novel c-di-GMP dependent cellular processes and unraveled c-di-GMP as an essential component of C. crescentus cell polarity and its bimodal life cycle. By varying cellular c-di-GMP concentrations, we determined dose response curves for individual c-di-GMP-dependent processes. Relating these values to c-di-GMP levels modeled for single cells progressing through the cell cycle sets a quantitative frame for the successive activation of c-di-GMP dependent processes during the C. crescentus life cycle. By reconstructing a simplified c-di-GMP network in a strain devoid of c-di-GMP we defined the minimal requirements for the oscillation of c-di-GMP levels during the C. crescentus cell cycle. Finally, we show that although all c-di-GMP dependent cellular processes were qualitatively restored by artificially adjusting c-di-GMP levels with a heterologous diguanylate cyclase, much higher levels of the second messenger are required under these conditions as compared to the contribution of homologous c-di-GMP metabolizing enzymes. These experiments suggest that a common c-di-GMP pool cannot fully explain spatiotemporal regulation by c-di-GMP in C. crescentus and that individual enzymes preferentially regulate specific phenotypes during the cell cycle.

Project description:BackgroundThe paired homeobox protein Pax6 is essential for proliferation and pluripotency of retinal progenitors. However, temporal changes in Pax6 protein expression associated with the generation of various retinal neurons have not been characterized with regard to the cell cycle. Here, we examine the dynamic changes of Pax6 expression among chicken retinal progenitors as they progress through the neurogenic cell cycle, and determine the effects of altered Pax6 levels on retinogenesis.ResultsWe provide evidence that during the preneurogenic to neurogenic transition, Pax6 protein levels in proliferating progenitor cells are down-regulated. Neurogenic retinal progenitors retain a relatively low level of Pax6 protein, whereas postmitotic neurons either elevate or extinguish Pax6 expression in a cell type-specific manner. Cell imaging and cell cycle analyses show that neurogenic progenitors in the S phase of the cell cycle contain low levels of Pax6 protein, whereas a subset of progenitors exhibits divergent levels of Pax6 protein upon entering the G2 phase of the cell cycle. We also show that M phase cells contain varied levels of Pax6, and some correlate with the onset of early neuronal marker expression, forecasting cell cycle exit and cell fate commitment. Furthermore, either elevating or knocking down Pax6 attenuates cell proliferation and results in increased cell death. Reducing Pax6 decreases retinal ganglion cell genesis and enhances cone photoreceptor and amacrine interneuron production, whereas elevating Pax6 suppresses cone photoreceptor and amacrine cell fates.ConclusionThese studies demonstrate for the first time quantitative changes in Pax6 protein expression during the preneurogenic to neurogenic transition and during the neurogenic cell cycle. The results indicate that Pax6 protein levels are stringently controlled in proliferating progenitors. Maintaining a relatively low Pax6 protein level is necessary for S phase re-entry, whereas rapid accumulation or reduction of Pax6 protein during the G2/M phase of the cell cycle may be required for specific neuronal fates. These findings thus provide novel insights on the dynamic regulation of Pax6 protein among neurogenic progenitors and the temporal frame of neuronal fate determination.

Dataset Information

Bi-modal reprogramming of cell cycle by MiRNA-4673 amplifies human neurogenic capacity.

Publications

Bi-modal reprogramming of cell cycle by MiRNA-4673 amplifies human neurogenic capacity.

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