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PubMed1987

Renal ultrastructural markers in AIDS-associated nephropathy.

Renal tissues from two groups of patients with acquired immune deficiency syndrome (AIDS) were examined: Group A had severe proteinuria and varying degrees of renal insufficiency, designated AIDS-associated nephropathy (AAN), and Group B had no renal involvement. Control Group C consisted of patients with heroin-associated nephropathy (HAN) with proteinuria comparable to patients in Group A but without AIDS or its related complex (ARC). The most frequent finding, common to both AAN and HAN, was focal glomerular sclerosis. In contrast to HAN, AAN tissue showed mesangial hypocellularity, sparse interstitial infiltrates, severe tubular degenerative changes, tubular microcystic ectasia, Bowman's space dilatation, and presence of multiple complex inclusions both in the nuclei and cytoplasm in a variety of cells. Abundant tubuloreticular inclusions were found in the endothelial and occasionally in the interstitial cell cytoplasm. Nuclear bodies (NBs) were seen in greater frequency, complexity, size, and heterogeneity, and of budding configuration in Group A as compared with Groups B and C; NBs in Group C were mostly of simple types (I and II). In addition, a peculiar granulofibrillary transformation in many tubular and interstitial cell nuclei was observed in Group A. This transformation was rarely present in Group B and was never seen in Group C. Because complex NBs (Types III to V) and various intracytoplasmic and intranuclear inclusions present in Group A are often associated with viral invasion, their presence in kidneys of AIDS patients with proteinuria suggests a viral etiology for AAN.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Visualizing the expression of a human growth hormone (hGH) transgene in the liver: intrahepatic regional and intracellular differences of expression are associated with morphological alterations and hepatocellular proliferation.

Growth hormone acts directly on liver cells; it binds to its receptor and induces a multitude of intracellular events leading, for example, to the production of insulin-like growth factor-1 (IGF-1). While much is known about the biochemical side of these events, their structural correlates are less well examined. Here, we examined livers of transgenic mice (TM) expressing human GH, in an attempt to correlate at the cellular level the site of GH gene expression with effects on morphology and mitotic behavior of liver cells within the hepatic architecture. Using in situ hybridization histochemistry we observed a striking expression pattern of the hGH gene in hepatocytes near the periportal spaces. In the same regions, the hGH protein, but no IGF-1 immunoreactive product, was detected using immunohistochemical methods. In the sections of TM livers, 6.8-31.9% of cells were hGH-immunoreactive. However, the cellular hGH staining pattern was not homogeneously distributed in the immunoreactive cells. Two main patterns became obvious. In the majority of the immunoreactive cells a cytoplasmic stain was present. These cells exhibited normal liver cell features and were not enlarged (type I). In the other group (type II), the staining was stronger and concentrated, sometimes punctuate, and often confined to cytoplasmic compartments which were in a perinuclear position. The latter staining pattern was generally seen in morphologically altered cells, which were enlarged and possessed intranuclear inclusions and invaginations. In the the periportal regions, mitotically active hepatocytes were evident, but these cells, as judged from immunocytochemistry, apparently did not express the transgene. In conclusion, different staining patterns for hGH may indicate different levels of transgene expression, which could be associated with difficulties in the cells with regard processing and/or secreting the hormone. In addition to the endocrine actions implied by the high hGH levels in the peripheral circulation of these TM, intracrine actions are also suggested (type II staining pattern), but para- and autocrine loops are possible as well (type I staining pattern). Whether IGF-1 is involved, and the mechanism underlying hepatocyte cell proliferation, remain to be examined.

Animals↗

PubMed2001

Effect of the pseudorabies virus US3 protein on nuclear membrane localization of the UL34 protein and virus egress from the nucleus.

The alphaherpesvirus UL34 protein is necessary for the primary envelopment of intranuclear capsids at the inner leaflet of the nuclear membrane. In herpes simplex virus type 1, the UL34 protein is exclusively phosphorylated by the protein kinase encoded by the non-essential US3 gene. To investigate the effect of the pseudorabies virus (PrV) US3 product on the intracellular localization of the UL34 protein and on virus morphogenesis, PrV US3 deletion mutants were isolated and characterized. Immunofluorescence analyses demonstrated that in the absence of the US3 protein, the localization of the UL34 polypeptide to the nuclear membrane was not as pronounced as that seen with US3, although immunoelectron microscopy indicated the presence of the UL34 protein in both leaflets of the nuclear membrane. Ultrastructurally, an accumulation of enveloped virions in the perinuclear space in large invaginations of the inner nuclear membrane was observed, which were shown by immunoelectron microscopy to contain the UL34 protein, but not glycoproteins gB or gC. Thus, the US3 protein appears to be involved in the de-envelopment of perinuclear virions by fusion with the outer leaflet of the nuclear membrane. Surprisingly, no difference in the phosphorylation of the PrV UL34 protein was observed in the presence or absence of the US3 kinase. Therefore, the observed effects of the PrV US3 protein on the intracellular localization of the UL34 protein and on virus morphogenesis are probably not due to the phosphorylation of the UL34 protein by the US3 kinase.

Cell Nucleus↗

PubMed2004

Signaling, internalization, and intracellular activity of fibroblast growth factor.

The fibroblast growth factor (FGF) family contains 23 members in mammals including its prototype members FGF-1 and FGF-2. FGFs have been implicated in regulation of many key cellular responses involved in developmental and physiological processes. These includes proliferation, differentiation, migration, apoptosis, angiogenesis, and wound healing. FGFs bind to five related, specific cell surface receptors (FGFRs). Four of these have intrinsic tyrosine kinase activity. Dimerization of the receptor is a prerequisite for receptor transphosphorylation and activation of downstream signaling molecules. All members of the FGF family have a high affinity for heparin and for cell surface heparan sulfate proteoglycans, which participate in formation of stable and active FGF-FGFR complexes. FGF-mediated signaling is an evolutionarily conserved signaling module operative in invertebrates and vertebrates. It seems that some members of the family have a dual mode of action. FGF-1, FGF-2, FGF-3, and FGF-11-14 have been found intranuclearly as endogenous proteins. Exogenous FGF-1 and FGF-2 are internalized by receptor-mediated endocytosis, in a clathrin-dependent and -independent way. Internalized FGF-1 and FGF-2 are able to cross cellular membranes to reach the cytosol and the nuclear compartment. The role of FGF internalization and the intracellular activity of some FGFs are discussed in the context of the known signaling induced by FGF.

Animals↗

PubMed1978

Nuclear surface complex as observed with the high resolution scanning electron microscope. Visualization of the membrane surfaces of the neclear envelope and the nuclear cortex from Xenopus laevis oocytes.

The nuclear envelope and associated structures from Xenopus laevis oocytes (stage VI) have been examined with the high resolution scanning electron microscope (SEM). The features of the inner and outer surfaces of the nuclear surface complex were revealed by manual isolation , whereas the membranes facing the perinuclear space (the space between the inner and outer nuclear membranes) were observed by fracturing the nuclear envelope in this plane and splaying the corresponding regions apart. Pore complexes were observed on all four membrane surfaces of this double-membraned structure. The densely packed pore complexes (55/micron2) are often clustered into triplets with shared walls (outer diameter = 90 nm; inner diameter = 25 nm; wall thickness = aproximately 30 nm), and project aproximately 20 nm above each membrane except where they are flush with the innermost surface. The pore complex appears to be an aggregate of four 30-nm subunits. The nuclear cortex, a fibrous layer (300 nm thickness) associated with the inner surface of the nuclear envelope, has been revealed by rapid fixation. This cortical layer is interrupted by funnel-shaped intranuclear channels (120-640 nm diam) which narrow towards the pore complexes. Chains of particles, arranged in spirals, are inserted into these intranuclear channels. The fibers associated with the innermost face of the nuclear envelope can be extraced with 0.6 MKI to reveal the pore complexes. A model of the nuclear surface complex, compiled from the visualization of all the membrane faces and the nuclear cortex, demonstrates relations between the intranuclear channels (3.2/micron2) and the numerous pore complexes, and the possibility of their role in nucleocytoplasmic interactions.

Animals↗

PubMed1977

[Ultra-fine organization of the goose coccidium Eimeria kotlani. I. Intranuclear development of macrogametes].

The ultrastructure of the macrogamete stage of Eimeria kotlani has been studied. The peculiarity of this eimerian parasite is that its development procedes within the host cell nucleus. The ultrastructure of the macrogamete of E. kotlani has much in common with that of other eimerians that are localized in the host cell cytoplasm. The differences noticed concern, first of all, the structural organization of wall forming bodies of both types (WF-1, WF-2). The WF-1 are originally arranged around the WF-2, as small electron opaque granules making a dark ring, to move towards the periphery of the macrogamete body with maturation. The WF-2 of E. kotlani macrogametes lack a labyrinth structure so characteristic of WF-2 of macrogametes of other eimerian species. The macrogamete of E. kotlani is limited with three membranes, the innermost membrane is interrupted. Pinocytosis is presumably a mode of the parasite's nutrition. The nutrients are supposed to be transported by vesicles originating from the nucleoplasm of the host cell and limited with two membranes. In result, the remaining nucleoplasm looks as a narrow space of small islets. The host cell cytoplasm reveals some degenerative changes only by the final step of the parasite's development.

Animals↗

PubMedDate not supplied

[Kaposi's sarcoma. A vascular neoplasm of presumably viral origin. Histologic and ultrastructural characteristics].

Kaposi's sarcoma is a multiform mesenchymal neoplasm of uncertain histogenesis but of possible viral origin. Several anatomo-clinical forms have been described the cutaneous nodular lesion being the most common and at highest frequency in equatorial Africa. Eighteen of such typical lesions were reported; their morphology was uniform and associated: 1) spindle cells, 2) an excess of vascular spaces composed of intratumoral intercellular slits and of intra and peritumoral well structured vessels, 3) a lymphoplasmocytic inflammatory infiltration. The lesions of the other and less common forms of Kaposi's sarcoma associated the same histological features in variable combination. At one end of the histological spectrum the lesions are essentially composed of irregular capillaries with few spindle cells, at the other end the tumor is a highly cellular neoplasm with few or no angiogenic features. The vascular structure of the typical lesions appeared clearly at the ultrastructural level. Most tumor cells were of endothelial type and formed cylinders with virtual or large central lumina, reminiscing of vascular sprouts. Pericyte-like cells were also present. In one the three ultrastructurally investigated cases, a tumor cell of the endothelial type contained intranuclear herpes virus like inclusions, group to which belongs the cytomegalovirus (CMV), a possible promoter of Kaposi's sarcoma.

Adolescent↗

PubMed2006

SAGA interacting factors confine sub-diffusion of transcribed genes to the nuclear envelope.

Changes in the transcriptional state of genes have been correlated with their repositioning within the nuclear space. Tethering reporter genes to the nuclear envelope alone can impose repression and recent reports have shown that, after activation, certain genes can also be found closer to the nuclear periphery. The molecular mechanisms underlying these phenomena have remained elusive. Here, with the use of dynamic three-dimensional tracking of a single locus in live yeast (Saccharomyces cerevisiae) cells, we show that the activation of GAL genes (GAL7, GAL10 and GAL1) leads to a confinement in dynamic motility. We demonstrate that the GAL locus is subject to sub-diffusive movement, which after activation can become constrained to a two-dimensional sliding motion along the nuclear envelope. RNA-fluorescence in situ hybridization analysis after activation reveals a higher transcriptional activity for the peripherally constrained GAL genes than for loci remaining intranuclear. This confinement was mediated by Sus1 and Ada2, members of the SAGA histone acetyltransferase complex, and Sac3, a messenger RNA export factor, physically linking the activated GAL genes to the nuclear-pore-complex component Nup1. Deleting ADA2 or NUP1 abrogates perinuclear GAL confinement without affecting GAL1 transcription. Accordingly, transcriptional activation is necessary but not sufficient for the confinement of GAL genes at the nuclear periphery. The observed real-time dynamic mooring of active GAL genes to the inner side of the nuclear pore complex is in accordance with the 'gene gating' hypothesis.

Diffusion↗

PubMed1995

Intranuclear distribution of galectin-3 in mouse 3T3 fibroblasts: comparative analyses by immunofluorescence and immunoelectron microscopy.

The intracellular distribution of carbohydrate binding protein 35 (CBP35), recently named galectin-3, was studied in mouse 3T3 fibroblasts, using immunofluorescence at the light microscope level and immunogold labeling at the ultrastructural level. In general, serum-stimulated, proliferating cells showed higher levels of labeling than quiescent cultures of the same cells. In the proliferating cells, the labeling intensity was higher in the nucleus than in the cytoplasm. Treatment of permeabilized cells or thin sections with ribonuclease A decreased the immunolabeling intensity, whereas parallel control treatments with deoxyribonuclease I failed to yield the same effect. While there appears to be general agreement between the immunofluorescence and the ultrastructural results regarding the level of CBP35 and its association with nuclear ribonucleoprotein complexes, there was one striking difference in terms of labeling of specific subnuclear structures. Immunofluorescence results indicate diffuse distribution of CBP35 within the nucleus, but the label appears to be excluded from certain "black holes," which most probably correspond to nucleoli. On the other hand, immunogold particles were observed in electron microscopy, mainly in interchromatin spaces, except for interchromatin granule clusters, at the border of condensed chromatin, on the dense fibrillar component, and at the periphery of the fibrillar centers of nucleoli.

3T3 Cells↗

PubMedDate not supplied

Calcium gradients in single smooth muscle cells revealed by the digital imaging microscope using Fura-2.

Calcium is believed to control a variety of cellular processes, often with a high degree of spatial and temporal precision. For a cell to use Ca2+ in this manner, mechanisms must exist for controlling the ion in a localized fashion. We have now gained insight into such mechanisms from studies which measured Ca2+ in single living cells with high resolution using a digital imaging microscope and the highly fluorescent Ca2+-sensitive dye, Fura-2. Levels of Ca2+ in the cytoplasm, nucleus and sarcoplasmic reticulum (SR) are clearly different. Free [Ca2+] in the nucleus and SR was greater than in the cytoplasm and these gradients were abolished by Ca2+ ionophores. When external Ca2+ was raised above normal in the absence of ionophores, free cytoplasmic Ca2+ increased but nuclear Ca2+ did not. Thus, nuclear [Ca2+] appears to be regulated independently of cytoplasmic [Ca2+] by gating mechanisms in the nuclear envelope. The observed regulation of intranuclear Ca2+ in these contractile cells may thus be seen as a way to prevent fluctuation in Ca2+-linked nuclear processes during the rise in cytoplasmic [Ca2+] which triggers contraction. The approach described here offers the opportunity of following changes in Ca2+ in cellular compartments in response to a wide range of stimuli, allowing new insights into the role of local changes in Ca2+ in the regulation of cell function.

Animals↗

PubMed2006

Neuronal atrophy and synaptic alteration in a mouse model of dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a hereditary spinocerebellar degeneration caused by expansion of a CAG repeat in the disease protein. Despite the restricted and stable brain lesions, DRPLA patients show a variety of clinical symptoms and the brain exhibits generalized atrophy. In previous studies of DRPLA, we proposed that intranuclear diffuse accumulation of the mutant protein is a significant pathological feature of neurons, and that the variable prevalence of this pathology may be relevant to the variation of symptoms observed in patients with different repeat sizes. In this study, to elucidate the pathogenesis of the brain atrophy in DRPLA, we conducted morphological and statistical analyses of neurons affected by the polyglutamine pathology in DRPLA transgenic (Tg) mice with 129 polyglutamine stretches. Golgi-impregnated pyramidal neurons in cerebral cortical layer V of 15-week-old Tg mice showed significant atrophy of the perikarya and dendrites. Dendritic spines were decreased in number and size, and showed a change in morphology resulting in dominance of stubby spines. Interestingly, dendritic arborization was preserved. Electron microscopy revealed that axons in the pyramis and corpus callosum were also atrophic. The number of axonal microtubules was preserved; however, the inter-microtubule spacing was significantly decreased. In the neuropil of cerebral cortical layers II and III, atrophy of the pre-synaptic areas and lengths of the post-synaptic density was detected, but synaptic vesicle diameter was preserved. These results suggest that neuronal atrophy is an essential feature of the cell pathology in DRPLA and that this is closely related to polyglutamine pathogenesis and development of the clinical phenotype.

Animals↗

PubMed1995

Perturbation of B cell genesis in the bone marrow of pristane-treated mice. Implications for plasmacytoma induction.

A single injection of pristane was given i.p. to plasmacytoma-susceptible BALB/cAn mice. At intervals up to 6 mo thereafter, immunofluorescence labeling of intranuclear terminal deoxynucleotidyl transferase (TdT), cell surface B220 glycoprotein, cytoplasmic mu-chains of IgM (c mu), and surface mu-chains (s mu), together with mitotic arrest techniques, were used to quantitate the in vivo population dynamics of precursor B cells in the bone marrow. TdT-expressing pro-B cells (TdT+B220-, TdT+B220+), before the expression of mu-chains, showed sustained increases in both population size and the number of cells flowing through mitosis per unit time. In contrast, populations of pre-B cells (c mu + s mu -) and B cells (s mu +) were consistently depressed for long periods of time, including the phase of plasmacytoma formation. Precursor B cells in DBA/2 mice, a plasmacytoma-resistant strain, showed similar responses to pristane treatment. The results demonstrate that a single injection of pristane, which greatly increases the demand for macrophage activity in the peritoneal space, causes sustained distant alterations in B cell lymphopoiesis in the bone marrow; specifically, a prolonged increased proliferation of pro-B cells coupled with a depression and a exaggerated loss of pre-B cells and B cells. The protracted stress on B cell lymphopoiesis may be a predisposing factor in the subsequent development of c-myc-activating chromosomal rearrangements that play a critical role in plasmacytomagenesis.

Animals↗

PubMed1986

Endocrine cells do not exist in rat Brunner's glands. An electron microscopic study.

It was revealed by light microscopic experiments that in Brunner's glands and the epithelium of the human and mammalian duodenum, cells were present, with basally lying granulations. These granules could be identified at the ultrastructural level as accumulations of pleomorphe electron-dense granules ('argentaffin', 'chromaffin' and 'osmiophilic' granules). Depending on the light and electron microscopic staining techniques used, these cells were classified as 'mucous', 'serous', or 'endocrine' ('enteroendocrine', 'paracrine' and 'enterochromaffin') cells. In the present study, the following ultrastructural morphological criteria of Brunner's gland cells were correlated: size, shape and electron density of their nuclei and nucleoli with morphological changes of their cytoplasmic and intranuclear organelles, which serve the synthesis of mucopeptides. This proved that the synthesis of mucopeptides occurred in 3 phases. The first phase served the intranuclear synthesis of organelles, which latterly were used for the cytoplasmic mucopeptide synthesis. This phase was characterized by the appearance of an electron-lucent and euchromatic nucleus, which also contained an euchromatic and electron-lucent nucleolus, and a thin electron-dense nucleus membrane (euchromatic phase). Only a few freely lying ribosomes, membrane-bound ribosomes (rough endoplasmic reticulum, RER) and mitochondria were dispersed throughout the cytoplasm. Therefore, the cytoplasm appeared electron-lucent and nearly empty. The second phase was characterized by a round but heterochromatical nucleus containing also a heterochromatic nucleolus, and the appearance of receptosome- (endosome, endocytotic vesicle) and lysosome-like structures near to the cytoplasmic membrane of the basal cell portion, as well as in the basal and lateral perinuclear region (early heterochromatic phase). The receptosome-like structures were round-oval and contained a single electron-lucent inclusion vesicle, which had an empty space or an electron-opaque granule. Both inclusion structures were located eccentrically on the inner surface of the membrane of the receptosome-like structure. Here and there, it was possible to visualize great receptosome-like structures (multivesicular bodies) containing numerous membranous electron-lucent and electron-opaque inclusion vesicles. Electron-dense pleomorphe lysosome-like structures, bearing 1-4 electron-lucent inclusion vesicles with faint grains in their spaces, were also recognized in the basal cell portion, as well as in the basal and lateral perinuclear region.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗

PubMed1977

Quantitative analysis of the digestion of yeast chromatin by staphylococcal nuclease.

The DNA in intranuclear yeast chromatin is protected from rapid staphylococcal nuclease degradation so as to yield an oligomeric series of DNA sizes. The course of production and disappearance of the various oligomers agrees quantitatively with a theory of random cleavage by the enzyme at uniformly susceptible sites. The sizes of the oligomers are integral repeats of a basic size, about 160 base pairs, and 80-90% of the yeast genome is involved in this repeating structure. Within this repeat there exists a 140 base pair core of more nuclease-resistant DNA. During the course of digestion, the sizes of the oligomers decrease continuously. The widths of the distribution of DNA sizes increase in order: monomer (1 X repeat size, half width = 5-7 base pairs) less than dimer (2 X repeat size, half width = 30 base pairs) less than trimer (3 X repeat size, half width = 40-45 base pairs). The yeast genome thus seems to have variable spacing of the nucleaseresistant cores, to produce the average repeat size of about 160 base pairs. Also, the presence of more than one species of monomer and dimer at certain times of digestion suggests a possible heterogeneity in the subunit structure.

Chromatin↗

PubMed2004

Haemolymph parasite of the shore crab Carcinus maenas: pathology, ultrastructure and observations on crustacean haplosporidians.

A protozoan parasite with some features of haplosporidians is described from the European shore crab Carcinus maenas. The parasite establishes a systemic infection through the haemal sinuses and connective tissues. Intracellular stages of the parasite were found within reserve inclusion, connective tissue, and muscle cells, while free forms were present in all haemal spaces. A uninucleate stage appeared to develop to a multinucleate plasmodial stage following multiple mitotic divisions of the nucleus. Histopathology also indicated that nuclear division may occur to form multinucleate plasmodia, in connective tissue, reserve inclusion and muscle cells, the multinucleate plasmodium being enclosed in the host-cell plasma membrane. It appears that the multinucleate plasmodium may then undergo internal cleavages which result in plasmodial fragmentation to form many uninucleate stages. Both stages, but particularly the uninucleate stage, contained cytoplasmic, large, ovoid, dense vesicles (DVs), some of which contained an internal membrane separating the medulla from the cortex, as in haplosporosomes. Golgi-like cisternae, closely associated with the nuclear membrane, formed DVs and haplosporosome-like bodies (HLBs), superficially resembling viruses. Infrequently, HLBs may condense to form haplosporosomes. The DVs, as in spores of some Haplosporidium spp. and paramyxeans, may give rise to, and are homologous with, haplosporosomes. Other features, such as the presence of an intranuclear mitotic spindle, lipid droplets, and attachment of DVs and haplosporosomes to the nuclear membrane, indicate that the C. maenas parasite is a haplosporidian. A similar organism reported from the haemolymph of spot prawns Pandalus spp., and haplosporidians reported from prawns Penaeus vannamei and crabs Callinectes sapidus may belong to this group. It is concluded that the well-characterised haplosporidians of molluscs and some other invertebrates may not be characteristic of the whole phylum, and that morphologically and developmentally similar organisms may also be haplosporidians, whether they have haplosporosomes or not.

Animals↗

PubMed2004

Inflammatory pseudotumor: a diagnostic dilemma in cytopathology.

Inflammatory pseudotumor (IPT) is a rare space-occupying lesion of unknown etiology that can mimic malignancy on clinicoradiological and pathological examination. A review of the cytopathology archives at The Johns Hopkins Hospital identified 12 cases from eight patients with histologically proven IPT (lung, seven patients; liver, five patients). There were six men and two women with an age range of 28-84 yr (mean age, 59 yr). Presenting complaints of IPT of the lung included shortness of breath and hemoptysis, and in cases of IPT of the liver complaints included abdominal pain and elevated liver function tests (LFTs). All cases were found to have mass lesions suspicious for a neoplasm on radiographic examination. Cytological specimens consisted of fine-needle aspiration (FNA; seven specimens) and bronchial brush/wash (five specimens). Diagnostic accuracy of cytology for IPT was low (5/12, 42%). IPT showed hypercellular smears (on FNA) with an admixture of various cell types including inflammatory cells with predominance of plasma cells, fibroblastic proliferation, granulation tissue formation, and atypical-appearing histiocytes with enlarged nuclei and intranuclear inclusions. Fibroblastic proliferation with mitoses may mimic mesenchymal neoplasms. Cytomorphology is nonspecific and IPT usually is a diagnosis of exclusion.

Adult↗

PubMed1995

Terminal transferase positive rat thymocytes are resistant to steroid-induced apoptosis.

Apoptosis is a prominent mechanism of programmed cell death in the immune system. In the thymus apoptosis is responsible for the deletion of autoreactive T-cells during thymic differentiation. The typical features of apoptosis are characterized by nuclear and cytoplasmic morphologic changes, along with cleavage of chromatin at regularly spaced sites. Terminal deoxynucleotidyl transferase (TdT) is a DNA polymerizing enzyme found at an early stage of T and B lymphocyte differentiation, which generates diversity in the DNA sequence of immunoglobulin (Ig) or T cell receptor (TCR). The combined evaluations of thymocyte morphological features, immune phenotype and thymic topography associated to TdT expression allow the recognition of three different thymocyte subpopulations, characterized by small-size, intermediate-size and large-size. The results of this study show that dexamethasone (Dx)-treatment induces cell death via apoptosis involving distinct transformations related to differentiation stages of thymic subpopulations. Intermediate and small-size thymocytes that are TdT-negative or weakly positive at nuclear level are Dx sensitive. In contrast the large-size thymocytes, highly TdT positive, corresponding to the undifferentiated cells, do not show significant morphological modifications and TdT positivity to Dx-treatment. Immunocytochemical analysis shows that Dx-treatment does not affect TdT synthesis but morphological changes, occurring during apoptotic process, are responsive to intracellular movement and intranuclear arrangement of the TdT.

Animals↗

PubMed2025

Nuclear rupture in confined cell migration triggers nuclear actin polymerization to limit chromatin leakage.

Upon cell migration in confined space, such as during cancer metastasis, mechanical forces from the extracellular matrix act onto the nucleus leading to nuclear envelope (NE) rupture, chromatin leakage and genomic instability. Here we found that during confined migration, NE rupture triggers dynamic nuclear F-actin formation dependent on the formins DIAPH1 and DIAPH3. We show that DIAPH3 dynamically and transiently relocates to the nucleus upon NE rupture. Interfering with DIAPH1/3 or with nuclear actin polymerization resulted in nuclear instability during confined migration. Notably, nuclear formin activity or actin assembly limit NE rupture-induced chromatin leakage. Similarly, silencing of Ataxia Telangiectasia and Rad3-related protein (ATR) reduced NE rupture-triggered nuclear F-actin assembly and increased chromatin leakage. Consistent with this, ATR promotes the phosphorylation of DIAPH3 at S1072 adjacent to its autoregulatory domain to promote nuclear actin polymerization. Using atomic force microscopy, we found that nuclear actin assembly or nuclear DIAPH3 activity promotes nuclear stiffness in an ATR-dependent manner. Thus, our study identifies an ATR-formin module that regulates nuclear mechanical properties through induction of intranuclear actin scaffolding.

Formins↗