Molecular and developmental mechanisms of anterior segment dysgenesis

Developmental Biology Unit, University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London, UK.
Eye (Impact Factor: 1.9). 11/2007; 21(10):1310-8. DOI: 10.1038/sj.eye.6702852
Source: PubMed

ABSTRACT Anterior segment dysgenesis (ASD) is a failure of the normal development of the tissues of the anterior segment of the eye. It leads to anomalies in the structure of the mature anterior segment, associated with an increased risk of glaucoma and corneal opacity. Several different gene mutations have been identified underlying these anomalies with the majority of ASD genes encoding transcriptional regulators. In this review, the role of the ASD genes, PITX2 and FOXC1, is considered in relation to the embryology of the anterior segment, the biochemical function of these proteins, and their role in development and disease aetiology. The emerging view is that these genes act in concert to specify a population of mesenchymal progenitor cells, mainly of neural crest origin, as they migrate anteriorly around the embryonic optic cup. These same genes then regulate mesenchymal cell differentiation to give rise to distinct anterior segment tissues. Development appears critically sensitive to gene dosage, and variation in the normal level of transcription factor activity causes a range of anterior segment anomalies. Interplay between PITX2 and FOXC1 in the development of different anterior segment tissues may partly explain the phenotypic variability and the genetic heterogeneity characteristic of ASD.

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    • "Key shows the color coding used to represent the embryonic origin of the anterior segment tissues in the right-hand plates, and the pattern of expression of the FOXC1 and PITX2 genes in the left-hand plates, based on published expression data. Reprinted with permission from (Sowden, 2007). "
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    ABSTRACT: The trabecular meshwork (TM) is located in the anterior segment of the eye and is responsible for regulating the outflow of aqueous humor. Increased resistance to aqueous outflow causes intraocular pressure to increase, which is the primary risk factor for glaucoma. TM cells reside on a series of fenestrated beams and sheets through which the aqueous humor flows to exit the anterior chamber via Schlemm's canal. The outer trabecular cells are phagocytic and are thought to function as a pre-filter. However, most of the outflow resistance is thought to be from the extracellular matrix (ECM) of the juxtacanalicular region, the deepest portion of the TM, and from the inner wall basement membrane of Schlemm's canal. It is becoming increasingly evident that the extracellular milieu is important in maintaining the integrity of the TM. In glaucoma, not only have ultrastructural changes been observed in the ECM of the TM, and a significant number of mutations in ECM genes been noted, but the stiffness of glaucomatous TM appears to be greater than that of normal tissue. Additionally, TGFβ2 has been found to be elevated in the aqueous humor of glaucoma patients and is assumed to be involved in ECM changes deep with the juxtacanalicular region of the TM. This review summarizes the current literature on trabecular ECM as well as the development and function of the TM. Animal models and organ culture models targeting specific ECM molecules to investigate the mechanisms of glaucoma are described. Finally, the growing number of mutations that have been identified in ECM genes and genes that modulate ECM in humans with glaucoma are documented. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Experimental Eye Research 04/2015; 133. DOI:10.1016/j.exer.2014.07.014 · 3.02 Impact Factor
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    • "Patients may also have systemic extraocular features including facial dysmorphism (maxillary hypoplasia, hypertelorism, telecanthus, prominent forehead), dental anomalies (hypodontia, microdontia), and/or redundant periumbilical skin. The condition is associated with raised intraocular pressure and an increased incidence of glaucoma affecting approximately 50% of patients has been reported [Idrees et al., 2006b; Sowden, 2007; Tumer and Bach- Holm, 2009]. AR segregates in an autosomal dominant manner. "
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    ABSTRACT: Disease-causing mutations affecting either one of the transcription factor genes, PITX2 or FOXC1, have been previously identified in patients with Axenfeld-Rieger syndrome (AR). We identified a family who segregate novel mutations in both PITX2 (p.Ser233Leu) and FOXC1 (c.609delC). The most severely affected individual, who presented with an atypical phenotype of corneal opacification, lens extrusion, persistent hyperplastic primary vitreous (PHPV), and subsequent bilateral retinal detachment, inherited mutations in both genes, whereas the single heterozygous mutations caused mild AR phenotypes. This is the first report of such digenic inheritance. By analyzing cognate targets of each gene, we showed that FOXC1 and PITX2 can independently regulate their own and each other's target gene promoters and do not show synergistic action in vitro. Mutation in either gene caused reduced transcriptional activation to different extents on the FOXO1 and PLOD1 promoters, whereas both mutations in combination showed the lowest level of activation. These data show how the compensatory activity of one factor, when the other is impaired, may lessen the phenotypic impact of developmental anomalies, yet reduced activity of both transcription factors increased disease severity. This suggests an under-reported mechanism for phenotypic variability whereby single mutations cause mild AR phenotypes, whereas digenic inheritance increases phenotypic severity.
    Human Mutation 10/2011; 32(10):1144-52. DOI:10.1002/humu.21550 · 5.05 Impact Factor
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    • "ASD is also associated with an increase in intraocular pressure (IOP) that leads to congenital glaucoma and lens defects such as congenital cataracts or aphakia (absence of the lens). ASD is genetically heterogeneous ; mutations in the transcription factor genes PITX2, PITX3, FOXC1, FOXE3, and PAX6 have been identified in patients with ASD, Axenfeld-Reiger syndrome, and dysgenesis of the lens (Gould and John, 2002; Sowden, 2007). "
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    ABSTRACT: Proper formation of the vertebrate eye requires a precisely coordinated sequence of morphogenetic events that integrate the developmental contributions of the skin ectoderm, neuroectoderm, and head mesenchyme. Disruptions in this process result in ocular malformations or retinal degeneration and can cause significant visual impairment. The zebrafish is an excellent vertebrate model for the study of eye development and disease due to the transparency of the embryo, its ex utero development, and its amenability to forward genetic screens. This review will present an overview of the genetic methodologies utilized in the zebrafish, a description of several zebrafish models of congenital ocular diseases, and a discussion of the utility of the zebrafish for assessing the pathogenicity of candidate disease alleles.
    Birth Defects Research Part C Embryo Today Reviews 09/2011; 93(3):215-28. DOI:10.1002/bdrc.20211 · 3.87 Impact Factor
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