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1.
PLoS One ; 8(1): e53183, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23382837

RESUMEN

BACKGROUND: Patent ductus arteriosus is a life-threatening condition frequent in premature newborns but also present in some term infants. Current mouse models of this malformation generally lead to perinatal death, not reproducing the full phenotypic spectrum in humans, in whom genetic inheritance appears complex. The ductus arteriosus (DA), a temporary fetal vessel that bypasses the lungs by shunting the aortic arch to the pulmonary artery, is constituted by smooth muscle cells of distinct origins (SMC1 and SMC2) and many fewer melanocytes. To understand novel mechanisms preventing DA closure at birth, we evaluated the importance of cell fate specification in SMC that form the DA during embryonic development. Upon specific Tyr::Cre-driven activation of Wnt/ß-catenin signaling at the time of cell fate specification, melanocytes replaced the SMC2 population of the DA, suggesting that SMC2 and melanocytes have a common precursor. The number of SMC1 in the DA remained similar to that in controls, but insufficient to allow full DA closure at birth. Thus, there was no cellular compensation by SMC1 for the loss of SMC2. Mice in which only melanocytes were genetically ablated after specification from their potential common precursor with SMC2, demonstrated that differentiated melanocytes themselves do not affect DA closure. Loss of the SMC2 population, independent of the presence of melanocytes, is therefore a cause of patent ductus arteriosus and premature death in the first months of life. Our results indicate that patent ductus arteriosus can result from the insufficient differentiation, proliferation, or contractility of a specific smooth muscle subpopulation that shares a common neural crest precursor with cardiovascular melanocytes.


Asunto(s)
Diferenciación Celular/fisiología , Conducto Arterioso Permeable/fisiopatología , Desarrollo Embrionario , Miocitos del Músculo Liso/patología , Nacimiento Prematuro/fisiopatología , Animales , Linaje de la Célula , Proliferación Celular , Conducto Arterioso Permeable/etiología , Femenino , Humanos , Melanocitos/citología , Ratones , Contracción Muscular/fisiología , Embarazo , Vía de Señalización Wnt
2.
Hum Mol Genet ; 19(8): 1561-76, 2010 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-20106872

RESUMEN

Adrenocortical carcinoma is a rare but aggressive cancer with unknown aetiology. Constitutive activation of beta-catenin is the most frequent alteration in benign and malignant adrenocortical tumours in patients. Here, we show that constitutive activation of beta-catenin in the adrenal cortex of transgenic mice resulted in progressive steroidogenic and undifferentiated spindle-shaped cells hyperplasia as well as dysplasia of the cortex and medulla. Over a 17 months time course, transgenic adrenals developed malignant characteristics such as uncontrolled neovascularization and loco-regional metastatic invasion. These oncogenic events were accompanied by ectopic differentiation of glomerulosa at the expense of fasciculata cells, which caused primary hyperaldosteronism. Altogether these observations demonstrate that constitutively active beta-catenin is an adrenal oncogene which triggers benign aldosterone-secreting tumour development and promotes malignancy.


Asunto(s)
Corteza Suprarrenal/patología , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/patología , beta Catenina/metabolismo , Corteza Suprarrenal/metabolismo , Neoplasias de las Glándulas Suprarrenales/fisiopatología , Aldosterona/metabolismo , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Humanos , Hiperplasia , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Metástasis de la Neoplasia
3.
Stem Cells ; 26(12): 3162-71, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18787210

RESUMEN

Ciliary epithelium (CE), which consists of nonpigmented and pigmented layers, develops from the optic vesicle. However, the molecular mechanisms underlying CE development have not been closely examined, in part because cell-surface markers suitable for specific labeling of subregions of the retina were unknown. Here, we identified CD138/syndecan-1 and stage specific embryonic antigen-1 (SSEA-1) CD15 as cell-surface antigens marking nonpigmented and pigmented CE, respectively. During retinal development, both CD138 and SSEA-1 were expressed in the early stage, and segregation of these markers in the tissue began at around embryonic day (E) 10. As a result, CD138-positive (CD138+) cells were found at the most distal tip of the retina, and SSEA-1+ cells were found in the periphery adjacent to the area of CD138 expression. In vitro characterization of isolated CD138+ or SSEA-1+ cell subpopulations revealed that CD138+ cells lose their retinal progenitor characteristics between E13 and E16, suggesting that they commit to becoming nonpigmented CE cells within this period. By in vivo mouse models, we found that stabilized beta-catenin expanded the area of CD138+ nonpigmented CE and that elimination of beta-catenin inhibited development of nonpigmented CE cells. These findings are the first to use cell-surface markers to ascertain the spatial and temporal transitions that occur in developing CE.


Asunto(s)
Cuerpo Ciliar/embriología , Epitelio/metabolismo , Regulación del Desarrollo de la Expresión Génica , Regulación de la Expresión Génica , Antígeno Lewis X/biosíntesis , Sindecano-1/biosíntesis , Proteínas Wnt/metabolismo , Alelos , Animales , Diferenciación Celular , Membrana Celular/metabolismo , Cuerpo Ciliar/metabolismo , Citometría de Flujo , Antígeno Lewis X/fisiología , Ratones , Ratones Endogámicos C57BL , Retina/citología , Retina/embriología , Sindecano-1/fisiología
4.
Stem Cells ; 26(5): 1337-46, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18356571

RESUMEN

Maintenance of classic stem cell hierarchies is dependent upon stem cell self-renewal mediated in part by Wnt/beta-catenin regulation of the cell cycle. This function is critical in rapidly renewing tissues due to the obligate role played by the tissue stem cell. However, the stem cell hierarchy responsible for maintenance of the conducting airway epithelium is distinct from classic stem cell hierarchies. The epithelium of conducting airways is maintained by transit-amplifying cells in the steady state; rare bronchiolar stem cells are activated to participate in epithelial repair only following depletion of transit-amplifying cells. Here, we investigate how signaling through beta-catenin affects establishment and maintenance of the stem cell hierarchy within the slowly renewing epithelium of the lung. Conditional potentiation of beta-catenin signaling in the embryonic lung results in amplification of airway stem cells through attenuated differentiation rather than augmented proliferation. Our data demonstrate that the differentiation-modulating activities of stabilized beta-catenin account for expansion of tissue stem cells.


Asunto(s)
Pulmón/citología , Células Madre/citología , Células Madre/metabolismo , beta Catenina/metabolismo , Animales , Bronquios/patología , Recuento de Células , Diferenciación Celular , Proliferación Celular , Cilios/ultraestructura , Células Epiteliales/citología , Células Epiteliales/ultraestructura , Pulmón/embriología , Ratones , Fenotipo , Fase S , Transducción de Señal , Células Madre/ultraestructura , Termodinámica , Cicatrización de Heridas
5.
Dev Cell ; 8(5): 751-64, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15866165

RESUMEN

Inactivation of beta-catenin in mesenchymal progenitors prevents osteoblast differentiation; inactivation of Lrp5, a gene encoding a likely Wnt coreceptor, results in low bone mass (osteopenia) by decreasing bone formation. These observations indicate that Wnt signaling controls osteoblast differentiation and suggest that it may regulate bone formation in differentiated osteoblasts. Here, we study later events and find that stabilization of beta-catenin in differentiated osteoblasts results in high bone mass, while its deletion from differentiated osteoblasts leads to osteopenia. Surprisingly, histological analysis showed that these mutations primarily affect bone resorption rather than bone formation. Cellular and molecular studies showed that beta-catenin together with TCF proteins regulates osteoblast expression of Osteoprotegerin, a major inhibitor of osteoclast differentiation. These findings demonstrate that beta-catenin, and presumably Wnt signaling, promote the ability of differentiated osteoblasts to inhibit osteoclast differentiation; thus, they broaden our knowledge of the functions Wnt proteins have at various stages of skeletogenesis.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/fisiología , Osteoblastos/citología , Osteoblastos/metabolismo , Osteoclastos/citología , Osteoclastos/metabolismo , Animales , Desarrollo Óseo , Diferenciación Celular , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Regulación del Desarrollo de la Expresión Génica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Hibridación in Situ , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas Relacionadas con Receptor de LDL , Operón Lac , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad , Ratones , Ratones Noqueados , Ratones Mutantes , Ratones Transgénicos , Osteogénesis , Osteopetrosis/etiología , Osteoprotegerina , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de LDL/deficiencia , Receptores de LDL/genética , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/metabolismo , Transducción de Señal , Transactivadores/genética , Transactivadores/metabolismo , Proteínas Wnt , beta Catenina
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