Browsing by Subject "Transcription factors"

Now showing 1 - 12 of 12
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    Different contribution of glucocorticoids in the basolateral amygdala to the formation and expression of opiate withdrawal-associated memories
    (Elsevier, 2016-10-08) Ferenczi, Szilamer; Kovács, Krisztina J.; Núñez Parra, Cristina; García Pérez, Daniel; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología; Facultades de la UMU::Facultad de Medicina
    Drug-withdrawal aversive memories generate a motivational state leading to compulsive drug taking, with plasticity changes in the basolateral amygdala (BLA) being essential in aversive motivational learning. The conditioned-place aversion (CPA) paradigm allows for measuring the negative affective component of drug withdrawal. First, CPA triggers association between negative affective consequences of withdrawal with context (memory consolidation). Afterwards, when the animals are re-exposed to the paired environment, they avoid it due to the association between the context and aversive memories (memory retrieval). We examined the influence of glucocorticoids (GCs) for a morphine-withdrawal CPA paradigm, along with plasticity changes in the BLA, in sham-operated and adrenalectomized (ADX) animals. We demonstrated that sham + morphine animals robustly displayed CPA, whereas ADX-dependent animals lacked the affective-like signs of opiate withdrawal but displayed increased somatic signs of withdrawal. Glucocorticoid receptor (GR) actions promote memory consolidation but highly depend on increases in GC levels. Interestingly, we observed that GCs were only increased in sham-dependent rodents during aversive-withdrawal memory consolidation, and that GR expression correlated with phosphorylated cAMP response element binding (pCREB) protein, early growth response 1 (Egr-1) and activity-regulated cytoskeletal-associated (Arc) mRNA induction in this experimental group. In contrast, ADX-animals displayed reduced (pCREB). GCs are also known to impair memory retrieval. Accordingly, we showed that GCs levels remained at basal levels in all experimental groups following memory retrieval, and consequently GRs no longer acted as transcriptional regulators. Importantly, memory retrieval elicited increased pCREB levels in sham + morphine animals (not in ADX + morphine group), which were directly correlated with enhanced Arc mRNA/protein expression mainly in glutamatergic neurons. In conclusion, context-withdrawal associations are accompanied plasticity changes in the BLA, which are, in part, regulated by GR signaling. Moreover, dysregulation of CREB signaling, in part through Arc expression, may enhance reconsolidation, resulting in the maintenance of excessive aversive states. These findings might have important implications for drug-seeking behavior.
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    Glucocorticoid homeostasis in the dentate gyrus is essential for opiate withdrawal-associated memories
    (Springer, 2016-10-11) García Pérez, Daniel; Ferenczi, Szilamer; Kovács, Krisztina J.; Núñez Parra, Cristina; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología; Facultad de Medicina
    Drug-withdrawal-associated aversive memories might trigger relapse to drug-seeking behavior. However, changes in structural and synaptic plasticity, as well as epigenetic mechanisms, which may be critical for long-term aversive memory, have yet to be elucidated. We used male Wistar rats and performed conditioned-place aversion (CPA) paradigm to uncover the role of glucocorticoids (GCs) on plasticity-related processes that occur within the dentate gyrus (DG) during opiate-withdrawal conditioning (memory formation-consolidation) and after reactivation by re-exposure to the conditioned environment (memory retrieval). Rats subjected to conditioned morphine-withdrawal robustly expressed CPA, while adrenalectomy impaired naloxone-induced CPA. Importantly, while activity-regulated cytoskeletal-associated protein (Arc) expression was induced in sham- and ADX-dependent animals during the conditioning phase, Arc and early growth response 1 (Egr-1) induction was restricted to sham-dependent rats following memory retrieval. Moreover, we found a correlation between Arc induction and CPA score, and Arc was selectively expressed in the granular zone of the DG in dopaminoceptive, glutamatergic and GABAergic neurons. We further found that brain-derived neurotrophic factor was regulated in the opposite way during the test phase. Our results also suggest a role for epigenetic regulation on the expression of glucocorticoid receptors and Arc following memory retrieval. Our data provide the first evidence that GC homeostasis is important for the expression of long-term morphine-withdrawal memories. Moreover, our results support the idea that targeting Arc and Egr-1 in the DG may provide important insights into the role of these signaling cascades in withdrawal-context memory re-consolidation. Together, disrupting these processes in the DG might lead to effective treatments in drug addiction thereby rapidly and persistently reducing invasive memories and subsequent drug seeking.
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    Histogenetic compartments of the mouse centromedial and extended amygdala based on gene expression patterns during development
    (Wiley, 2007-11-07) García López, Margarita; Abellán, Antonio; Legaz Pérez, Isabel; Rubenstein, John L. R.; Puelles, Luis; Medina, Loreta; Ciencias Sociosanitarias
    The amygdala controls emotional and social behavior and regulates instinctive reflexes such as defense and reproduction by way of descending projections to the hypothalamus and brainstem. The descending amygdalar projections are suggested to show a cortico-striato-pallidal organization similar to that of the basal ganglia (Swanson [2000] Brain Res 886:113–164). To test this model we investigated the embryological origin and molecular properties of the mouse centromedial and extended amygdalar subdivisions, which constitute major sources of descending projections. We analyzed the distribution of key regulatory genes that show restricted expression patterns within the subpallium (Dlx5, Nkx2.1, Lhx6, Lhx7/8, Lhx9, Shh, and Gbx1), as well as genes considered markers for specific subpallial neuronal subpopulations. Our results indicate that most of the centromedial and extended amygdala is formed by cells derived from multiple subpallial subdivisions. Contrary to a previous suggestion, only the central—but not the medial—amygdala derives from the lateral ganglionic eminence and has striatal-like features. The medial amygdala and a large part of the extended amygdala (including the bed nucleus of the stria terminalis) consist of subdivisions or cell groups that derive from subpallial, pallial (ventral pallium), or extratelencephalic progenitor domains. The subpallial part includes derivatives from the medial ganglionic eminence, the anterior peduncular area, and possibly a novel subdivision, called here commissural preoptic area, located at the base of the septum and related to the anterior commissure. Our study provides a molecular and morphological foundation for understanding the complex embryonic origins and adult organization of the centromedial and extended amygdala.
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    Intracellular signaling modifications involved in the anti-inflammatory effect of 4-alkoxy-6,9-dichloro[1,2,4]triazolo[4,3-a]quinoxalines on macrophages
    (Elsevier, 2017-01-03) Tristán-Manzano, María; Guirado, Antonio; Gálvez, Jesús; García-Peñarrubia, Pilar; Martínez-Esparza Alvargonzález, María Concepción; Ruiz Alcaraz, Antonio José; Bioquímica y Biología Molecular B e Inmunología
    Inflammation is part of a complex biological response directed by the immune system to fight pathogens and maintain homeostasis. Dysregulation of the inflammatory process leads to development of chronic inflammatory or autoimmune diseases. Several cell types, such as macrophages, and cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) are involved in the regulation of inflammation. The important role played by these cytokines asmediators of the inflammatory process and the side effects of current therapies have promoted the search of new therapeutic alternatives. Quinoxalines are important compounds allowing a wide range of chemical modifications in order to provide an extensive repertoire of biological activities. We have previously shown that a series of 4-alkoxy-6,9-dichloro[1,2,4]triazolo[4,3-a]quinoxalines exhibit potent anti-inflammatory activity, inhibiting the production of TNF-α and IL-6. Our aim here was to study the mechanism thereby this series of compounds act upon different intracellular signaling pathways to uncover their potential molecular targets. By using immunoblotting assays, we found that these compounds inhibit ERK 1/2 and JNK/c-Jun cascades, and reduce c-Fos expression, while activate the anti-inflammatory PI3K/Akt route. These results provide further information on their effect upon the intracellular signal transduction mechanisms leading to inhibition of TNF-α and IL-6 secretion. Our results may be of great interest for the pharmaceutical industry, and could be used as a starting point for the development of new and more potent anti-inflammatory drugs derived from the quinoxaline core.
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    Mechanisms of regulation of normal and metaplastic intestinal differentiation
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Rodrigues, Jaime P.; David, Leonor; Almeida, Raquel; Barros, Rita; Freitas, Teresa; Ponte, Ana; Sousa, Mafalda; Silva, João Carlos; Carvalho, João
    The gastrointestinal tract is an organized structure originating from the three embryonic germ layers: endoderm, mesoderm and ectoderm. Morphological changes that accompany its formation are relatively well known, although the underlying molecular mechanisms are still poorly defined. Intestinal metaplasia, resulting from an epithelial transdifferentiation process, is considered a precursor lesion of gastric adenocarcinoma, a malignancy with serious consequences in terms of morbidity and mortality worldwide. Similarly to gastrointestinal embryonic development, molecular changes involved in the development of this lesion that recapitulate the intestinal development, out of time and space, are also widely unknown. In this review we present, briefly, the process of formation of the digestive tract, from its embryonic age to adulthood, with emphasis on anterior-posterior patterning and on molecular mechanisms that may play an important role. In addition, we try to establish a parallel and understand what mechanisms can, through their deregulation, originate the metaplastic lesion. Cdx genes appear to be the main regulators of normal intestinal differentiation and also to be largely involved in the metaplastic epithelial transdifferentiation process. However, control of gene expression both during intestinal development and in intestinal metaplasia is complex and seems to depend on several transcription factors. More extensive studies about the mechanisms underlying intestinal metaplasia are needed if we aim to prevent neoplasia development and all its negative consequences in persons at risk.
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    Molecular mechanisms in dental follicle precursor cells during the osteogenic differentiation
    (F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Morsczeck, Christian
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    Molecular Segmentation of the Spinal Trigeminal Nucleus in the Adult Mouse Brain
    (Frontiers Media, 2021-12-10) García-Guillén, Isabel M.; Martínez-de-la-Torre, Margaret; Puelles, Luis; Aroca Tejedor, Pilar; Marín San Leandro, Faustino; Anatomía Humana y Psicobiología
    The trigeminal column is a hindbrain structure formed by second order sensory neurons that receive afferences from trigeminal primary (ganglionic) nerve fibers. Classical studies subdivide it into the principal sensory trigeminal nucleus located next to the pontine nerve root, and the spinal trigeminal nucleus which in turn consists of oral, interpolar and caudal subnuclei. On the other hand, according to the prosomeric model, this column would be subdivided into segmental units derived from respective rhombomeres. Experimental studies have mapped the principal sensory trigeminal nucleus to pontine rhombomeres (r) r2-r3 in the mouse. The spinal trigeminal nucleus emerges as a plurisegmental formation covering several rhombomeres (r4 to r11 in mice) across pontine, retropontine and medullary hindbrain regions. In the present work we reexamined the issue of rhombomeric vs. classical subdivisions of this column. To this end, we analyzed its subdivisions in an AZIN2-lacZ transgenic mouse, known as a reference model for hindbrain topography, together with transgenic reporter lines for trigeminal fibers. We screened as well for genes differentially expressed along the axial dimension of this structure in the adult and juvenile mouse brain. This analysis yielded genes from multiple functional families that display transverse domains fitting the mentioned rhombomeric map. The spinal trigeminal nucleus thus represents a plurisegmental structure with a series of distinct neuromeric units having unique combinatorial molecular profiles.
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    Multiple regionalized genes and their putative Networks in the interpeduncular nucleus suggest complex mechanisms of neuron development and axon guidance
    (Frontiers Media, 2021-02-16) García-Guillén, Isabel M.; Puelles López, Luis; Alonso Fuentes, Antonia; Aroca Tejedor, Pilar; Marín San Leandro, Faustino; Anatomía Humana y Psicobiología
    The interpeduncular nucleus (IPN) is a highly conserved limbic structure in the vertebrate brain, located in the isthmus and rhombomere 1. It is formed by various populations that migrate from different sites to the distinct domains within the IPN: the prodromal, rostral interpeduncular, and caudal interpeduncular nuclei. The aim here was to identify genes that are differentially expressed across these domains, characterizing their putative functional roles and interactions. To this end, we screened the 2,038 genes in the Allen Developing Mouse Brain Atlas database expressed at E18.5 and we identified 135 genes expressed within the IPN. The functional analysis of these genes highlighted an overrepresentation of gene families related to neuron development, cell morphogenesis and axon guidance. The interactome analysis within each IPN domain yielded specific networks that mainly involve members of the ephrin/Eph and Cadherin families, transcription factors and molecules related to synaptic neurotransmission. These results bring to light specific mechanisms that might participate in the formation, molecular regionalization, axon guidance and connectivity of the different IPN domains. This genoarchitectonic model of the IPN enables data on gene expression and interactions to be integrated and interpreted, providing a basis for the further study of the connectivity and function of this poorly understood nuclear complex under both normal and pathological conditions.
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    The dexamethasone induced osteogenic differentiation of dental follicle cells
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Morsczeck, Christian; Reichert, Torsten E.
    Mesenchymal stem cells are excellent for in vitro studies about biological processes during the differentiation of osteogenic progenitor cells into mineralizing cells such as osteoblasts. Human dental follicle cells (DFCs) are dental mesenchymal stem cells and they can be isolated from third molar teeth. Because DFCs are the genuine progenitor cells of periodontal tissue cells, they have been used for the evaluation of molecular mechanisms during the differentiation of undifferentiated stem cells into alveolar osteoblasts and cementoblasts. To reveal molecular mechanisms of osteogenic differentiation, initial studies investigated the proteome and the transcriptome of DFCs after the induction of the osteogenic differentiation with the glucocorticoid dexamethasone. These studies showed for example that dexamethasone induces the transcription factor ZBTB16 (zinc finger and BTB domain containing protein 16) and that ZBTB16 is crucial for osteogenic differentiation of DFCs. This article is a survey of the molecular mechanisms in DFCs during osteogenic differentiation with dexamethasone.
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    Transcription regulators are transiently expressed during the prostate gland adaptation to the hypoandrogenic environment
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2019) Nishan, Umar; Rosa Ribeiro, Rafaela; Lenz Cesar, Carlos; Carvalho, Hernandes F.
    The high incidence of prostatic diseases, including malignant tumors, makes the understanding of prostate biology very important. Androgen deprivation, blockade by orchiectomy, or chemical castration causes prostate and tumor shrinkage. The gene networks involved in a cell type-specific fashion are rather unknown. This work was undertaken to identify genes with annotated function in transcription regulation that might define transitions in gene expression. A total of 15 potential regulatory genes were identified. Validation by qRT-PCR showed that Zfp703 and Arid1a exhibit expression maxima at day 1; Ash2l, Nelf, Pbx3, Eya2 at day 4; Dmrt2 at day 5 and Lbh and Sox1 at day 7 after castration. Using immunohistochemistry, we further determined that PBX3 was found in both stromal and epithelial cells, whereas ARID1A and NELF were restricted to the epithelium, and DMRT2 and EYA2 were exclusively found in the stroma. Though the proteins ZFP703 and ASH2l were not found in any experimental condition, their mRNAs were located by in situ hybridization in both epithelium and stroma. In conclusion, androgen deprivation triggers the expression of temporally regulated gene sets in both epithelial and stromal cells. These gene subsets will help establish the regulatory gene expression programs orchestrating the castration-induced remodeling of the prostate gland, and represent putative targets to increase the efficacy of androgen-deprivation to induce epithelial (and cancer) cell death.
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    Transfecting Taxus x media protoplasts to study transcription factors BIS2 and TSAR2 as activators of taxane-related genes
    (Oxford University Press, 2020-03) Sánchez Muñoz, Raul; Cusido, Rosa M.; Bonfill, Mercedes; Palazón, Javier; Moyano, Elisabeth; Almagro Romero, Lorena; Biología Vegetal
    Taxane diterpenes are secondary metabolites with an im-portant pharmacological role in the treatment of cancer. Taxus spp. biofactories have been used for taxane produc-tion, but the lack of knowledge about the taxane biosynthet-ic pathway and its molecular regulation hinders their optimal function. The difficulties in introducing foreign genes in Taxus spp. genomes hinder the study of the mo-lecular mechanisms involved in taxane production, and a new approach is required to overcome them. In this study, a reliable, simple and fast method to obtain Taxus 􀀁 media protoplasts was developed, allowing their manipulation in downstream assays for the study of physiological changes in Taxus spp. cells. Using this method, Taxus protoplasts were transiently transfected for the first time, corroborating their suitability for transfection assays and the study of specific physiological responses. The two assayed transcription fac-tors (BIS2 and TSAR2) had a positive effect on the expression of several taxane-related genes, suggesting their potential use for the improvement of taxane yields. Furthermore, the results indicate that the developed method is suitable for obtaining T. 􀀁 media protoplasts for transfection with the aim of unraveling regulatory mechanisms in tax-ane production.
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    Zinc finger proteins and regulation of the hallmarks of cancer
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2019) Ye, Qin; Liu, Jiayang; Xie, Ke
    Zinc finger proteins (ZFPs) form one of the largest families of transcription factors in human genetics, via their conserved zinc finger motifs. ZFPs function in many biological processes including development, differentiation, metabolism and apoptosis. In addition, recent studies have demonstrated that ZFPs are closely associated with different stages of cancer development. One of the hallmarks of cancer is altered signal transduction cascades and an understanding of the changes in these pathways is essential for targeted cancer therapy. In this review, we discuss examples of ZFPs involved in development and progression of several types of cancer, which can provide new insights into cancer treatment