Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

Beukelaers, Pierre; Vandenbosch, Renaud; Caron, Nicolas; Nguyen, Laurent; Belachew, Shibeshih; Moonen, Gustave; Kiyokawa, Hiroaki; Barbacid, Mariano; Santamarı́a, David; Malgrange, Brigitte

doi:10.1002/stem.616

Cited by 56 publications

(52 citation statements)

References 72 publications

(100 reference statements)

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“…In the early G 1 phase, cell cycle progression is driven by the concerted action of Cdk4 and Cdk6, whereas Cdk2 is the driving force during late G 1 phase [44]. It has already been shown that Cdk6, but not Cdk4 or Cdk2, is required for AHN [33,45]. In addition, to ensuring correct progression through the cell cycle, there are internal checkpoints that monitor the conditions to generate healthy daughter cells, and cell damage or stress may restrict cell cycle progression and/or induce cell death, through them.…”

Section: Discussionmentioning

confidence: 99%

Smad3 is required for the survival of proliferative intermediate progenitor cells in the dentate gyrus of adult mice

et al. 2013

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BackgroundNew neurons are continuously being generated in the adult hippocampus, a phenomenon that is regulated by external stimuli, such as learning, memory, exercise, environment or stress. However, the molecular mechanisms underlying neuron production and how they are integrated into existing circuits under such physiological conditions remain unclear. Indeed, the intracellular modulators that transduce the extracellular signals are not yet fully understood.ResultsWe show that Smad3, an intracellular molecule involved in the transforming growth factor (TGF)-β signaling cascade, is strongly expressed by granule cells in the dentate gyrus (DG) of adult mice, although the loss of Smad3 in null mutant mice does not affect their survival. Smad3 is also expressed by adult progenitor cells in the subgranular zone (SGZ) and more specifically, it is first expressed by Type 2 cells (intermediate progenitor cells). Its expression persists through the distinct cell stages towards that of the mature neuron. Interestingly, proliferative intermediate progenitor cells die in Smad3 deficiency, which is associated with a large decrease in the production of newborn neurons in Smad3 deficient mice. Smad3 signaling appears to influence adult neurogenesis fulfilling distinct roles in the rostral and mid-caudal regions of the DG. In rostral areas, Smad3 deficiency increases proliferation and promotes the cell cycle exit of undifferentiated progenitor cells. By contrast, Smad3 deficiency impairs the survival of newborn neurons in the mid-caudal region of the DG at early proliferative stages, activating apoptosis of intermediate progenitor cells. Furthermore, long-term potentiation (LTP) after high frequency stimulation (HFS) to the medial perforant path (MPP) was abolished in the DG of Smad3-deficient mice.ConclusionsThese data show that endogenous Smad3 signaling is central to neurogenesis and LTP induction in the adult DG, these being two forms of hippocampal brain plasticity related to learning and memory that decline with aging and as a result of neurological disorders.

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Section: Discussionmentioning

confidence: 99%

Smad3 is required for the survival of proliferative intermediate progenitor cells in the dentate gyrus of adult mice

et al. 2013

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“…Among them is the ability of CDK6 to modulate differentiation in specific cell types including murine erythroid leukemia, primary mouse astrocytes, osteoblasts and osteoclasts, thymocytes, neurons, cardiomyocytes and hematopoietic cells. [22][23][24][25][26][27][28][29][30][31] In hematopoietic cells, for example, down-regulation of CDK6 allows terminal differentiation due to the release of runt-related transcription factor 1 (Runx1), a transcriptional factor required for the opening of chromatin of important hematopoietic regulator genes. 27 Location of CDK6 CDK6 has been shown to reside in the cytoplasm of many cell types.…”

Section: Introductionmentioning

confidence: 99%

Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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Cyclin-dependent kinase 6 (CDK6) plays a vital role in regulating the progression of the cell cycle. More recently, CDK6 has also been shown to have a transcriptional role in tumor angiogenesis. Up-regulated CDK6 activity is associated with the development of several types of cancers. While CDK6 is over-expressed in cancer cells, it has a low detectable level in non-cancerous cells and CDK6-null mice develop normally, suggesting a specific oncogenic role of CDK6, and that its inhibition may represent an ideal mechanism-based and low toxic therapeutic strategy in cancer treatment. Identification of selective small molecule inhibitors of CDK6 is thus needed for drug development. Herein, we review the latest understandings of the biological regulation and oncogenic roles of CDK6. The potential clinical relevance of CDK6 inhibition, the progress in the development of small-molecule CDK6 inhibitors and the rational design of potential selective CDK6 inhibitors are also discussed.

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“…Furthermore, G1 lengthens specifically during acquisition of a neurogenic fate (Calegari et al, 2005) and during transition from apical progenitors to basal progenitors that are already committed to neuron production (Arai et al, 2011). In addition, numerous cell cycle regulators have been shown to affect stem cell fate, including cyclins and CDK inhibitors (Doetsch et al, 2002b;Kowalczyk et al, 2004;Kippin et al, 2005;Beukelaers et al, 2011). Prolongation of G1 by chemical inhibition of CDK2-cyclin E (Calegari and Huttner, 2003) or by RNAi-mediated silencing of CDK4-cyclin D (Lange et al, 2009) resulted in increased neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

Predicting stem cell fate changes by differential cell cycle progression patterns

et al. 2013

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SUMMARYStem cell self-renewal, commitment and reprogramming rely on a poorly understood coordination of cell cycle progression and execution of cell fate choices. Using existing experimental paradigms, it has not been possible to probe this relationship systematically in live stem cells in vitro or in vivo. Alterations in stem cell cycle kinetics probably occur long before changes in phenotypic markers are apparent and could be used as predictive parameters to reveal changes in stem cell fate. To explore this intriguing concept, we developed a single-cell tracking approach that enables automatic detection of cell cycle phases in live (stem) cells expressing fluorescent ubiquitylation-based cell-cycle indicator (FUCCI) probes. Using this tool, we have identified distinctive changes in lengths and fluorescence intensities of G1 (red fluorescence) and S/G2-M (green) that are associated with self-renewal and differentiation of single murine neural stem/progenitor cells (NSCs) and embryonic stem cells (ESCs). We further exploited these distinctive features using fluorescence-activated cell sorting to select for desired stem cell fates in two challenging cell culture settings. First, as G1 length was found to nearly double during NSC differentiation, resulting in progressively increasing red fluorescence intensity, we successfully purified stem cells from heterogeneous cell populations by their lower fluorescence. Second, as ESCs are almost exclusively marked by the green (S/G2-M) FUCCI probe due to their very short G1, we substantially augmented the proportion of reprogramming cells by sorting green cells early on during reprogramming from a NSC to an induced pluripotent stem cell state. Taken together, our studies begin to shed light on the crucial relationship between cell cycle progression and fate choice, and we are convinced that the presented approach can be exploited to predict and manipulate cell fate in a wealth of other mammalian cell systems.

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Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

Cited by 56 publications

References 72 publications

Smad3 is required for the survival of proliferative intermediate progenitor cells in the dentate gyrus of adult mice

Smad3 is required for the survival of proliferative intermediate progenitor cells in the dentate gyrus of adult mice

Targeting CDK6 in cancer: State of the art and new insights

Predicting stem cell fate changes by differential cell cycle progression patterns

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