Cell Cycle Commitment and the Origins of Cell Cycle Variability

Exit of cells from quiescence following mitogenic stimulation is highly asynchronous, and there is a great deal of heterogeneity in the response. Even in a single, clonal population, some cells re-enter the cell cycle after a sub-optimal mitogenic signal while other, seemingly identical cells, do not, though they remain capable of responding to a higher level of stimulus. This review will consider the origins of this variability and heterogeneity, both in cells re-entering the cycle from quiescence and in the context of commitment decisions in continuously cycling populations. Particular attention will be paid to the role of two interacting molecular networks, namely the RB-E2F and APC/CCDH1 “switches.” These networks have the property of bistability and it seems likely that they are responsible for dynamic behavior previously described kinetically by Transition Probability models of the cell cycle. The relationship between these switches and the so-called Restriction Point of the cell cycle will also be considered.

Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages

Background Colony-stimulating factor 1 (CSF1) expression in the central nervous system (CNS) increases in response to a variety of stimuli, and CSF1 is overexpressed in many CNS diseases. In young adult mice, we previously showed that CSF1 overexpression in the CNS caused the proliferation of IBA1+ microglia without promoting the expression of M2 polarization markers. Methods Immunohistochemical and molecular analyses were performed to further examine the impact of CSF1 overexpression on glia in both young and aged mice. Results As CSF1 overexpressing mice age, IBA1+ cell numbers are constrained by a decline in proliferation rate. Compared to controls, there were no differences in expression of the M2 markers ARG1 and MRC1 (CD206) in CSF1 overexpressing mice of any age, indicating that even prolonged exposure to increased CSF1 does not impact M2 polarization status in vivo. Moreover, RNA-sequencing confirmed the lack of increased expression of markers of M2 polarization in microglia exposed to CSF1 overexpression but did reveal changes in expression of other immune-related genes. Although treatment with inhibitors of the CSF1 receptor, CSF1R, has been shown to impact other glia, no increased expression of oligodendrocyte lineage or astrocyte markers was observed in CSF1 overexpressing mice. Conclusions Our study indicates that microglia are the primary glial lineage impacted by CSF1 overexpression in the CNS and that microglia ultimately adapt to the presence of the CSF1 mitogenic signal.

Genome instability as an indicator of environmental state in the Murmansk region

The data of various researchers indicate that the combined effects of natural and anthropogenic factors directly affect the nature of the territorial morbidity of the inhabitants of the Far North. In biomonitoring of the environment, a micronucleus test on human cells is widely used to assess the degree of genotoxicity of the comparison areas. The aim of the research is to study the local situation with the accumulation of lesions in the lymphocytes of children living in the Murmansk region using a micronucleus test. As a result of assessing the cytogenetic status of the child population living in the comparison territories (Krasnoshchelye, Lovozero, Umba, Apatity), specific territorial features of the cytogenetic status of children were revealed, which are probably associated with the prevailing morbidity in the territories comparisons. This is probably due to territorial genotoxic and toxic agents. Significant differences in the frequency of occurrence of binucleated lymphocytes with micronuclei in schoolchildren were noted when all cells (mononuclear, binuclear, trinuclear, quadrenuclear cells, as well as cells containing more than 4 nuclei) were taken into account between Krasnoshchelye, Lovozero (U = 45.0, p = 0.0009), Umba (U = 91.0, p = 0.0125) and Apatity (U = 113.0, p = 0.0125). Also, significant differences were noted between the frequency of occurrence of cells with micronuclei among cells that did not respond to the mitogenic signal (mononuclear) and contain more than 2 nuclei in lymphocytes between adolescents from Krasnoshchelye and Apatity (U = 109.0, p = 0.0093) and Umba (U = 73.5, p = 0.0025). When comparing the frequency of occurrence of all types of cells containing micronuclei in the lymphocytes of adolescents, significant differences were revealed between the frequency of occurrence of such cells in adolescents from Apatity and Umba (U = 97.0, p = 0.0036).

Mi-2/NuRD complex protects stem cell progeny from mitogenic Notch signaling

To progress towards differentiation, progeny of stem cells need to extinguish expression of stem-cell maintenance genes. Failures in such mechanisms can drive tumorigenesis. In Drosophila neural stem cell (NSC) lineages, excessive Notch signalling results in supernumerary NSCs causing hyperplasia. However, onset of hyperplasia is considerably delayed implying there are mechanisms that resist the mitogenic signal. Monitoring the live expression of a Notch target gene, E(spl)mγ, revealed that normal attenuation is still initiated in the presence of excess Notch activity so that re-emergence of NSC properties occurs only in older progeny. Screening for factors responsible, we found that depletion of Mi-2/NuRD ATP remodeling complex dramatically enhanced Notch-induced hyperplasia. Under these conditions, E(spl)mγ was no longer extinguished in NSC progeny. We propose that Mi-2 is required for decommissioning stem-cell enhancers in their progeny, enabling the switch towards more differentiated fates and rendering them insensitive to mitogenic factors such as Notch.

Mi-2/NuRD complex protects stem cell progeny from mitogenic Notch signaling

To progress towards differentiation, the progeny of stem cells need to extinguish expression of stem cell maintenance genes. Failures in these mechanisms that suppress stem cell programmes can lead to supernumerary stem cells and drive tumorigenesis. In Drosophila neural stem cell lineages, excessive Notch signalling results in supernumerary stem cells causing hyperplasia. But the onset of hyperplasia is considerably delayed implying there are mechanisms that resist the mitogenic signal. Monitoring live the expression of an early NSC marker, the Notch target gene E(spl)mγ, revealed that the normal process of NSC fate attenuation is still initiated even in the presence of excess Notch activity so that the re-emergence of stem cell properties occurs only in older progeny. Screening for factors responsible, we found that depletion of Mi-2 and other members of the NuRD ATP remodeling complex dramatically enhanced the Notch-induced hyperplasia. Under these conditions, E(spl)mγ was no longer extinguished in the stem cell progeny, but instead remained at high levels. We propose that Mi-2 is required for decommissioning stem cell enhancers in their progeny, enabling the switch towards a more differentiated fate and rendering them insensitive to mitogenic factors such as Notch.