RESUMEN
PURPOSE: The zinc finger transcription factor Zeb1 binds to E-box-like sequences and is important for maintaining repression of epithelial specification genes in vivo. Overexpression of Zeb1 in cancer triggers epithelial-mesenchymal transition, which facilitates metastasis. The mutation of ZEB1 in humans is linked to posterior polymorphous corneal dystrophy (PPCD), in which an epithelial transition of the corneal endothelium is associated with abnormal endothelial proliferation. The purpose of this study is to determine whether Zeb1 null or heterozygous mice may provide an animal model for PPCD. METHODS: Corneal morphology, protein and mRNA expression, and cell proliferation were compared in wild-type and Zeb1 gene knockout mice by immunostaining, real-time PCR, and BrdU incorporation. mRNA expression in isolated embryo fibroblasts derived from wild-type, Zeb1 heterozygous, and null mice was analyzed by real-time PCR RESULTS: Zeb1 null mice late in gestation show ectopic expression of epithelial genes in the corneal endothelium and keratocytes, including the basement membrane component COL4A3, which is ectopically expressed by the corneal endothelium in PPCD. These embryos also show abnormal corneal endothelial and keratocyte proliferation, corneal thickening, and corneolenticular and iridocorneal adhesions. Adult Zeb1 heterozygous mice exhibit these same corneal defects. The ectopic expression of epithelial genes extended to embryonic fibroblasts derived from Zeb1 heterozygous and null mice, suggesting that Zeb1 may have a more general role in the suppression of an epithelial phenotype. CONCLUSIONS: The authors conclude that Zeb1 heterozygous and null mice show features of PPCD and thus should provide an animal model for genetic dissection of pathways contributing to the disease.
Asunto(s)
Distrofias Hereditarias de la Córnea/genética , Modelos Animales de Enfermedad , Endotelio Corneal/metabolismo , Proteínas de Homeodominio/fisiología , Factores de Transcripción de Tipo Kruppel/fisiología , Mutación/fisiología , Dedos de Zinc/fisiología , Animales , Autoantígenos/genética , Autoantígenos/metabolismo , Bromodesoxiuridina/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Proliferación Celular , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Distrofias Hereditarias de la Córnea/embriología , Distrofias Hereditarias de la Córnea/patología , Endotelio Corneal/embriología , Endotelio Corneal/patología , Epitelio Corneal/embriología , Epitelio Corneal/metabolismo , Epitelio Corneal/patología , Femenino , Fibroblastos/metabolismo , Técnica del Anticuerpo Fluorescente Indirecta , Dosificación de Gen , Genotipo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
Current thinking on the embryological origin of human corneal endothelium has it that this cellular population stems from neural crest precursors. There are arguments in support of this assumption but equally persuasive ones against it. We present a discussion of the evidence for and against a neural crest origin for human corneal endothelial cells. In suggesting that caution be applied to extrapolating from non-human work, we would question the fallibility of the current thinking on this subject. To denote human corneal dystrophies as neurocristopathies may be a premature assumption.
Asunto(s)
Distrofias Hereditarias de la Córnea/embriología , Cresta Neural/embriología , Animales , Embrión de Pollo , Endotelio Corneal/embriología , Humanos , Melanocitos/citología , Codorniz/embriologíaRESUMEN
BACKGROUND: A decisive condition for the clarification of malformations and degenerations is knowledge of the pre- and postnatal development. Therefore investigations were undertaken to determine the plan and lay-out of the eye-lids in an hairloss mutant of mouse. MATERIALS AND METHODS: Biomicroscopical and histological investigations were carried out in 51 hl-mice from the 10th day of gestation unto the birth. This particular mouse is a spontaneous hairloss mutant, in which corneal degenerations also occur. RESULTS: On the 11th day of gestation the ectodermal dips may be distinguished, as well as the shoe-lace-like furrows around the eye-ball, which indicate the development of the eyelids. The upper and lower lid are formed by proliferation. The fusion of the eyelids is completed around the 16th day of gestation. DISCUSSION: The eyelid development starts in mice between the 11th and 14th day of gestation. The fusion is completed on day 15-17. The morphogenesis of the eyelid development will be discussed.
Asunto(s)
Distrofias Hereditarias de la Córnea/embriología , Párpados/anomalías , Ratones Pelados/embriología , Ratones Mutantes/embriología , Animales , Párpados/embriología , Genes Dominantes , Edad Gestacional , Ratones , ConejosRESUMEN
The cornea from an early developing and uncomplicated case of posterior polymorphous dystrophy in a 15-year-old boy shows a thin abnormal Descemet's membrane and reduced number of endothelial cells as the primary findings. Ultrastructurally, the membrane was composed of a very thin, three-dimensional lattice pattern layer covered by layers of fibrous material. This lattice pattern is normally formed between late fetal and early adolescent life. The 3 previously reported histologic cases of this entity were from cases with long-standing corneal opacities in the late third to fifth decade of life with additional corneal changes. However, in each case the lattice pattern layer of the membrane was abnormally thin. This report suggests that a progressive form of posterior polymorphous dystrophy of the cornea is due to cells forming abnormal Descemet's membrane beginning in late fetal life to soon after birth.