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1.
EMBO J ; 38(9)2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-30886049

RESUMEN

Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a ß-catenin-independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9-positive Lef1-negative hair follicle progenitors that give rise to the upper SG Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.


Asunto(s)
Factor de Transcripción GATA6/metabolismo , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Factor de Unión 1 al Potenciador Linfoide/fisiología , Neoplasias de las Glándulas Sebáceas/patología , Neoplasias Cutáneas/patología , Células Madre/patología , Animales , Proliferación Celular , Daño del ADN , Femenino , Folículo Piloso/metabolismo , Folículo Piloso/patología , Humanos , Factor de Unión 1 al Potenciador Linfoide/genética , Masculino , Ratones , Ratones Noqueados , Homólogo 1 de la Proteína MutL/genética , Homólogo 1 de la Proteína MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Mutación , Neoplasias de las Glándulas Sebáceas/genética , Neoplasias de las Glándulas Sebáceas/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Células Madre/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
2.
Dev Biol ; 313(2): 533-44, 2008 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-18068152

RESUMEN

Both dramatic and subtle morphogenetic movements are of paramount importance in molding cells and tissues into functional form. Cells move either independently or as populations and the distance traversed by cells varies greatly, but in all cases, the output is common: to organize cells into or within organs and epithelia. In the developing Drosophila eye, a highly specialized, 90 degrees rotational movement of subsets of cells imposes order by polarizing the retinal epithelium across its dorsoventral axis. This process was proposed to take place in two 45 degrees steps, with the second under control of the gene nemo (nmo), a serine/threonine kinase. While our analysis confirms that these subsets of cells, the ommatidial precursors, do stall at 45 degrees , we demonstrate that nmo is also required through most of the first 45 degrees of rotation to regulate the speed at which the ommatidial precursors move. In addition, although the precursors reach only the halfway point by the end of larval life, this work demonstrates that patterning events that occur during pupal life move the ommatidial units an additional 15 degrees . A re-analysis of nmo mosaic clones indicates that nmo is required in photoreceptors R1, R6 and R7 for normal orientation. This work also demonstrates that two major isoforms of nmo rescue the nmo(P1) phenotype. Finally, a dominant modifier screen of a nmo misexpression background identified genomic regions that potentially regulate rotation. The results presented here suggest a model in which a motor for rotation is established in a nemo-dependent fashion in a subset of cells.


Asunto(s)
Proteínas de Drosophila/fisiología , Ojo/citología , Proteínas Quinasas Activadas por Mitógenos/fisiología , Células Fotorreceptoras de Invertebrados/fisiología , Rotación , Alelos , Animales , Animales Modificados Genéticamente , Polaridad Celular , Clonación Molecular , Drosophila/citología , Drosophila/genética , Drosophila/crecimiento & desarrollo , Proteínas de Drosophila/genética , Ojo/ultraestructura , Proteínas Fluorescentes Verdes/metabolismo , Hibridación in Situ , Metamorfosis Biológica/fisiología , Proteínas Quinasas Activadas por Mitógenos/genética , Modelos Biológicos , Mutación , Células Fotorreceptoras de Invertebrados/citología , Isoformas de Proteínas/química , Isoformas de Proteínas/fisiología , Retina/citología , Retina/crecimiento & desarrollo , Retina/fisiología , Transgenes
3.
Dev Biol ; 310(2): 348-62, 2007 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-17826761

RESUMEN

The adult Drosophila retina is a highly polarized epithelium derived from a precursor tissue that is initially symmetric across its dorsoventral axis. Specialized 90 degrees rotational movements of subsets of cells, the ommatidial precursors, establish mirror symmetry in the retinal epithelium. Myosin II, or Zipper (Zip), a motor protein, regulates the rate at which ommatidia rotate: in zip mutants, the rate of rotation is significantly slowed. Zip is concentrated in the cells that we show to be at the likely interface between rotating and non-rotating cells: the boundary between differentiated and undifferentiated cells. Zip is also robust in newly added ommatidial cells, consistent with our model that the machinery that drives rotation should shift to newly recruited cells as they are added to the growing ommatidium. Finally, cell death genes and canonical Wnt signaling pathway members genetically modify the zip phenotype.


Asunto(s)
Proteínas de Drosophila/fisiología , Drosophila/citología , Proteínas de la Membrana/fisiología , Cadenas Pesadas de Miosina/fisiología , Retina/fisiología , Animales , Diferenciación Celular , Movimiento Celular , Drosophila/crecimiento & desarrollo , Proteínas de Drosophila/genética , Proteínas de la Membrana/genética , Mutación , Cadenas Pesadas de Miosina/genética , Células Fotorreceptoras de Invertebrados/fisiología , Retina/citología , Retina/crecimiento & desarrollo , Transducción de Señal , Proteínas Wnt/metabolismo
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