Nuclear envelope defects cause stem cell dysfunction in premature-aging mice

et al.Nuclear lamina alterations occur in physiological aging and in premature aging syndromes. Because aging is also associated with abnormal stem cell homeostasis, we hypothesize that nuclear envelope alterations could have an important impact on stem cell compartments. To evaluate this hypothesis, we examined the number and functional competence of stem cells in Zmpste24 -null progeroid mice, which exhibit nuclear lamina defects. We show that Zmpste24 deficiency causes an alteration in the number and proliferative capacity of epidermal stem cells. These changes are associated with an aberrant nuclear architecture of bulge cells and an increase in apoptosis of their supporting cells in the hair bulb region. These alterations are rescued in Zmpste24 -/- Lmna+/- mutant mice, which do not manifest progeroid symptoms. We also report that molecular signaling pathways implicated in the regulation of stem cell behavior, such as Wnt and microphthalmia transcription factor, are altered in Zmpste24-/- mice. These findings establish a link between age-related nuclear envelope defects and stem cell dysfunction.This work was supported by grants from Ministerio de Educacion y Ciencia (Spain), Fundación Lilly, Fundación La Caixa, Fundación M. Botín, and the European Union. I. Flores is a Ramón y Cajal senior scientist. M.A. Blasco´s laboratory is funded by the Ministerio de Ciencia y Tecnologia (Spain), the regional government of Madrid, the European Union, and Josef Steiner Cancer Research Award 2003. The Instituto Universitario de Oncología is supported by Obra Social Cajastur.Peer Reviewe

A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis

Canonical Wnt signaling is critically involved in normal hematopoietic development and the self-renewal process of hematopoietic stem cells (HSCs). Deregulation of this pathway has been linked to a large variety of cancers, including different subtypes of leukemia. Lef-1 is a major transcription factor of this pathway and plays a pivotal role in lymphoid differentiation as well as in granulopoiesis. Here, we demonstrate Lef-1 expression in murine HSCs as well as its expression in human leukemia. Mice transplanted with bone marrow retrovirally transduced to express Lef-1 or a constitutive active Lef-1 mutant showed a severe disturbance of normal hematopoietic differentiation and finally developed B lymphoblastic and acute myeloid leukemia (AML). Lef-1–induced AMLs were characterized by immunoglobulin (Ig) DH-JH rearrangements and a promiscuous expression of lymphoid and myeloid regulatory factors. Furthermore, single cell experiments and limiting dilution transplantation assays demonstrated that Lef-1–induced AML was propagated by a leukemic stem cell with lymphoid characteristics displaying Ig DH-JH rearrangements and a B220+ myeloid marker− immunophenotype. These data indicate a thus far unknown role of Lef-1 in the biology of acute leukemia, pointing to the necessity of balanced Lef-1 expression for an ordered hematopoietic development

Nuclear envelope defects cause stem cell dysfunction in premature-aging mice

Nuclear lamina alterations occur in physiological aging and in premature aging syndromes. Because aging is also associated with abnormal stem cell homeostasis, we hypothesize that nuclear envelope alterations could have an important impact on stem cell compartments. To evaluate this hypothesis, we examined the number and functional competence of stem cells in Zmpste24-null progeroid mice, which exhibit nuclear lamina defects. We show that Zmpste24 deficiency causes an alteration in the number and proliferative capacity of epidermal stem cells. These changes are associated with an aberrant nuclear architecture of bulge cells and an increase in apoptosis of their supporting cells in the hair bulb region. These alterations are rescued in Zmpste24−/−Lmna+/− mutant mice, which do not manifest progeroid symptoms. We also report that molecular signaling pathways implicated in the regulation of stem cell behavior, such as Wnt and microphthalmia transcription factor, are altered in Zmpste24−/− mice. These findings establish a link between age-related nuclear envelope defects and stem cell dysfunction

Surface Heterogeneity of Tumor Cells and Changes Upon Ionizing Radiation

Heterogeneous distribution of surface domains is a characteristic feature of the tumor cell surface and the distribution differs from that of normal cells. During the malignant transformation the heterogeneity may change or disappear. Cell lines with various metastasizing capacities show different distributions of membrane domains or other differences in membrane or surface organization. We have demonstrated that the amount and distribution of negatively charged sites of B 16 melanoma membranes changed upon ionizing radiation (X-ray, 60Co-gamma). In the case of the P 388 lymphoma, however, only the amount of negatively charged sites change after irradiation, the distribution remains unaltered. Both features proved to be radioresistant in human lymphoid leukemic cells

Exploring Self and Emotion: Unamuno´s Narrative Fiction as Thought Experiment

In this paper, I explore Unamuno’s narrative fictions as thought experiments about self and emotion. I begin by developing a notion of thought experiment consequent with his understanding of philosophy as a form of literature. Next, I focus on the philosophy of the emotions implicit in his major essay Del Sentimiento trágico de la vida. The third section offers a case study in the form of envy in the novel Abel Sánchez. The final section addresses different forms of knowledge about the emotions conveyed by Unamuno’s fictional works

Gossip as an interpersonal communication phenomenon

Two studies were conducted for the purpose of validating Foster\u27s (2004) Gossip Functions Questionnaire (GFQ) which measures the reasons why people gossip (i.e., the functions of gossip). The GFQ originally consisted of four subscales that measured the functions of gossip: information, entertainment, friendship, and influence. In Study One, an exploratory factor analysis failed to reveal the four subscales Foster originally conceptualized. However, three factors were apparent that seemed to measure three separate functions of gossip: trivial gossip, influential gossip, and behavioral guidance gossip. In Study Two, a confirmatory factor analysis of a second data set failed to validate the 3-factor Gossip Functions Questionnaire. It was also proposed that the GFQ would be related to indirect interpersonal aggression, Machiavellianism, and tendency to gossip. The data from Study Two indicated that the 3-factor Gossip Functions Questionnaire was, in fact, significantly positively related to each of the variables above

The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells

The adhesion molecule L1, which is extensively characterized in the nervous system, is also expressed in dendritic cells (DCs), but its function there has remained elusive. To address this issue, we ablated L1 expression in DCs of conditional knockout mice. L1-deficient DCs were impaired in adhesion to and transmigration through monolayers of either lymphatic or blood vessel endothelial cells, implicating L1 in transendothelial migration of DCs. In agreement with these findings, L1 was expressed in cutaneous DCs that migrated to draining lymph nodes, and its ablation reduced DC trafficking in vivo. Within the skin, L1 was found in Langerhans cells but not in dermal DCs, and L1 deficiency impaired Langerhans cell migration. Under inflammatory conditions, L1 also became expressed in vascular endothelium and enhanced transmigration of DCs, likely through L1 homophilic interactions. Our results implicate L1 in the regulation of DC trafficking and shed light on novel mechanisms underlying transendothelial migration of DCs. These observations might offer novel therapeutic perspectives for the treatment of certain immunological disorders

Las emociones y la naturalización de la intencionalidad

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