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Cell Cycle Exit (cell + cycle_exit)
Selected AbstractsLocalization of Indian hedgehog and PTH/PTHrP receptor expression in relation to chondrocyte proliferation during mouse bone developmentDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 2 2005Helen E. MacLean We have developed a useful approach to examine the pattern of gene expression in comparison to cell proliferation, using double in situ hybridization and immunofluorescence. Using this system, we examined the expression of Indian hedgehog (Ihh) and PTH/PTHrP receptor (PPR) mRNA in relation to chondrocyte proliferation during embryonic mouse bone development. Both genes are expressed strongly in prehypertrophic and early hypertrophic chondrocytes, and there is a strong correlation between upregulation of both Ihh and PPR expression and chondrocyte cell cycle arrest. At embryonic day (E14.5), PPR mRNA upregulation begins in the columnar chondrocytes just prior to cell cycle exit, but at later time points expression is only observed in the postproliferative region. In contrast, Ihh mRNA expression overlaps slightly with the region of columnar proliferating chondrocytes at all stages. This study provides further evidence that in the developing growth plate, cell cycle exit and upregulation of Ihh and PPR mRNA expression are coupled. [source] Zac1 promotes a Müller glial cell fate and interferes with retinal ganglion cell differentiation in Xenopus retinaDEVELOPMENTAL DYNAMICS, Issue 1 2007Lin Ma Abstract The timing of cell cycle exit is tightly linked to cell fate specification in the developing retina. Accordingly, several tumor suppressor genes, which are key regulators of cell cycle exit in cancer cells, play critical roles in retinogenesis. Here we investigated the role of Zac1, a tumor suppressor gene encoding a zinc finger transcription factor, in retinal development. Strikingly, in gain-of-function assays in Xenopus, mouse Zac1 promotes proliferation and apoptosis at an intermediate stage of retinogenesis. Zac1 also influences cell fate decisions, preferentially promoting the differentiation of tumor-like clusters of abnormal neuronal cells in the ganglion cell layer, as well as inducing the formation of supernumerary Müller glial cells at the expense of other cell types. Thus Zac1 has the capacity to influence cell cycle exit, and cell fate specification and differentiation decisions by retinal progenitors, suggesting that further functional studies will uncover new insights into how retinogenesis is regulated. Developmental Dynamics 236:192,202, 2007. © 2006 Wiley-Liss, Inc. [source] The rho GTPase Rac1 is required for proliferation and survival of progenitors in the developing forebrainDEVELOPMENTAL NEUROBIOLOGY, Issue 9 2010Dino P. Leone Abstract Progenitor cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing forebrain give rise to neurons and glial cells, and are characterized by distinct morphologies and proliferative behaviors. The mechanisms that distinguish VZ and SVZ progenitors are not well understood, although the homeodomain transcription factor Cux2 and Cyclin D2, a core component of the cell cycle machinery, are specifically involved in controlling SVZ cell proliferation. Rho GTPases have been implicated in regulating the proliferation, differentiation, and migration of many cell types, and one family member, Cdc42, affects the polarity and proliferation of radial glial cells in the VZ. Here, we show that another family member, Rac1, is required for the normal proliferation and differentiation of SVZ progenitors and for survival of both VZ and SVZ progenitors. A forebrain-specific loss of Rac1 leads to an SVZ-specific reduction in proliferation, a concomitant increase in cell cycle exit, and premature differentiation. In Rac1 mutants, the SVZ and VZ can no longer be delineated, but rather fuse to become a single compact zone of intermingled cells. Cyclin D2 expression, which is normally expressed by both VZ and SVZ progenitors, is reduced in Rac1 mutants, suggesting that the mutant cells differentiate precociously. Rac1-deficient mice can still generate SVZ-derived upper layer neurons, indicating that Rac1 is not required for the acquisition of upper layer neuronal fates, but instead is needed for the normal regulation of proliferation by progenitor cells in the SVZ. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 659,678, 2010 [source] Glutamate regulates retinal progenitors cells proliferation during developmentEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2006Rodrigo A. P. Martins Abstract The precise coordination of cell cycle exit and cell fate specification is essential for generating the correct proportion of retinal cell types during development. The decision to exit the cell cycle is regulated by intrinsic and extrinsic cues. There is growing evidence that neurotransmitters can regulate cell proliferation and cell fate specification during the early stages of CNS development prior to the formation of synaptic connections. We found that the excitatory neurotransmitter glutamate regulates retinal progenitor cell proliferation during embryonic development of the mouse. AMPA/kainate and N -methyl- d -aspartate receptors are expressed in embryonic retinal progenitor cells. Addition of exogenous glutamate leads to a dose-dependent decrease in cell proliferation without inducing cell death or activating the p53 pathway. Activation of AMPA/kainate receptors induced retinal progenitor cells to prematurely exit the cell cycle. Using a replication-incompetent retrovirus to follow the clonal expansion of individual retinal progenitor cells, it was observed that blockade of AMPA/kainate receptors increased the proportion of large clones, showing that modulation of endogenous glutamatergic activity can have long-term consequences on retinal cell proliferation. Real time reverse transcriptase-polymerase chain reaction and immunoblot analyses demonstrated that glutamate does not alter the levels of the mRNA and proteins that regulate the G1/S-phase transition. Instead, the activity of the Cdk2 kinase is reduced in the presence of glutamate. These data indicate that glutamate regulates retinal progenitor cell proliferation by post-translational modulation of cyclin/Cdk2 kinase activity. [source] Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell linesFEBS JOURNAL, Issue 16 2004Georgia Xouri Licensing origins for replication upon completion of mitosis ensures genomic stability in cycling cells. Cdt1 was recently discovered as an essential licensing factor, which is inhibited by geminin. Over-expression of Cdt1 was shown to predispose cells for malignant transformation. We show here that Cdt1 is down-regulated at both the protein and RNA level when primary human fibroblasts exit the cell cycle into G0, and its expression is induced as cells re-enter the cell cycle, prior to S phase onset. Cdt1's inhibitor, geminin, is similarly down-regulated upon cell cycle exit at both the protein and RNA level, and geminin protein accumulates with a 3,6 h delay over Cdt1, following serum re-addition. Similarly, mouse NIH3T3 cells down-regulate Cdt1 and geminin mRNA and protein when serum starved. Our data suggest a transcriptional control over Cdt1 and geminin at the transition from quiescence to proliferation. In situ hybridization and immunohistochemistry localize Cdt1 as well as geminin to the proliferative compartment of the developing mouse gut epithelium. Cdt1 and geminin levels were compared in primary cells vs. cancer-derived human cell lines. We show that Cdt1 is consistently over-expressed in cancer cell lines at both the protein and RNA level, and that the Cdt1 protein accumulates to higher levels in individual cancer cells. Geminin is similarly over-expressed in the majority of cancer cell lines tested. The relative ratios of Cdt1 and geminin differ significantly amongst cell lines. Our data establish that Cdt1 and geminin are regulated at cell cycle exit, and suggest that the mechanisms controlling Cdt1 and geminin levels may be altered in cancer cells. [source] Modelling cellular senescence as a result of telomere stateAGING CELL, Issue 3 2003Carole J. Proctor Summary Telomeres in mammalian cells end in large duplex T loops. These loops protect the single-strand overhangs from degradation and/or interactions with signalling proteins. This protection is sometimes referred to as capping. At each cell division, telomeres shorten and there is a general consensus that telomere shortening triggers cell cycle exit. However, the exact mechanism by which telomere shortening causes cell cycle arrest is not known. Mathematical models of telomere shortening have been developed to help us understand the processes involved. Until now most models have assumed that the trigger for cell cycle arrest is the first telomere or a group of telomeres reaching a critically short length. However, there is evidence that cells stop cycling over a wide range of telomere lengths. This suggests that telomere length per se may not in fact be the trigger for cellular senescence. In this paper we develop a model which examines the hypothesis that uncapping of a telomere is the main trigger. By letting the probability of uncapping depend upon telomere length, we show that the hypothesized model provides a good fit to experimental data. [source] The transcription factor ATF5: role in neurodevelopment and neural tumorsJOURNAL OF NEUROCHEMISTRY, Issue 1 2009Lloyd A. Greene Abstract We review recent findings regarding the properties of ATF5 and the major roles that this transcription factor plays in development of the nervous system and in survival of neural tumors. ATF5 is a widely expressed basic leucine zipper protein that has been subject to limited characterization. It is highly expressed in zones of neuroprogenitor cell proliferation. In vitro and in vivo studies indicate that it functions there to promote neuroprogenitor cell expansion and to suppress their differentiation into neurons or glia. ATF5 expression is down-regulated by trophic factors and this is required for their capacity to promote neuroprogenitor cell cycle exit and differentiation into either neurons, oligodendroglia or astrocytes. ATF5 is also highly expressed in a number of tumor types, including neural tumors such as neuroblastomas, medulloblastomas and glioblastomas. Examination of the role of ATF5 in glioblastoma cells indicates that interference with its expression or activity causes them to undergo apoptotic death. In contrast, normal astrocytes and neurons do not appear to require ATF5 for survival, indicating that it may be a selective target for treatment of glioblastomas and other neural neoplasias. Further studies are needed to identify the transcriptional targets of ATF5 and the mechanisms by which its expression is regulated in neuroprogenitors and tumors. [source] AUF1 and Hu proteins in the developing rat brain: Implication in the proliferation and differentiation of neural progenitorsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2009Dolores Hambardzumyan Abstract Posttranscriptional events such as RNA stabilization are important for cell differentiation, but little is known about the impact of AU-rich binding proteins (AUBPs) on the fate of neural cells. Expression of destabilizing AUBPs such as AUF1 and neuronal-specific stabilizing proteins such as HuB, HuC and HuD was therefore analyzed in the developing central nervous system. Real-time RT-PCR indicated a specific developmental pattern in the postnatal cerebellum, with a progressive down-regulation of AUF1 from P1, whereas HuB was strongly up-regulated at about P7. These changes were accompanied by a progressive increase in AUF1p45 and the disappearance of one HuB isoform from P15, suggesting particular roles for these AUBPs in the developing cerebellum. AUF1 was detected in the three main cerebellar layers, whereas Hu proteins were found only in postmitotic neurons. A role for Hu proteins in the early stages of neuronal differentiation is further supported by arrest of cell proliferation following induction of HuB or HuD expression in a neural stem cell line. The decrease in nestin expression suggest that HuD, but not HuB, favors the transition of neural progenitors into early neuroblasts, but other factors are most probably required for their full differentiation into neurons, insofar as GAP-43 was not detected in HuD-transfected cells. These data suggest critical roles for HuB at the very earliest stages of neuronal differentiation, such as cell cycle exit, and HuD might also be involved in the transition of neural progenitors into early neuroblasts. Taken together, the present results strengthen the importance of AUBPs in brain ontogenesis. © 2008 Wiley-Liss, Inc. [source] Endothelial nitric oxide synthase deficiency in mice results in reduced chondrocyte proliferation and endochondral bone growthARTHRITIS & RHEUMATISM, Issue 7 2010Qian Yan Objective Nitric oxide (NO) and aberrant chondrocyte differentiation have both been implicated in the pathogenesis of osteoarthritis, but whether these processes are connected is unknown, and the role of specific NO synthase (NOS) enzymes in chondrocyte physiology is unclear. This study was undertaken to examine the effects of inactivation of endothelial cell NOS (eNOS) on cartilage development in mice. Methods Skeletal growth and development of mice carrying a null mutation in the eNOS gene was compared with that of their control littermates. In situ analyses were complemented by experiments with primary chondrocytes and tibial explants from these mice. Results Mice that were deficient in eNOS showed increased fatality and reduced bone growth, with hypocellular growth plates and a marked reduction in the number of proliferating chondrocytes. In vitro studies demonstrated lower chondrocyte numbers and reduced endochondral bone growth in mutant mice, suggesting that the role of eNOS signaling in chondrocyte proliferation is cell autonomous. Reduced chondrocyte numbers appear to be caused by decreased cyclin D1 and increased p57 expression in mutant mice, resulting in slower cell cycle progression and earlier cell cycle exit. In addition, expression of early chondrocyte markers such as SOX9 was reduced, and prehypertrophic markers were expressed prematurely in mutant mice. Conclusion Our findings identify a novel and important role of eNOS in chondrocyte proliferation and endochondral bone growth and demonstrate that loss of eNOS results in premature cell cycle exit and prehypertrophic chondrocyte differentiation during cartilage development. [source] | ||||||||||