Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse corneas from wildtype vs. corneas under the influence of high doses of TGF-beta

ABSTRACT: Characteristic structural details of the cornea are transparency, the absence of blood vessels, and the presence of numerous sensory nerve endings. The corneal epithelium is one of the most densely innervated tissues of the body. The characteristics of the cornea are established during fetal development, and are lost in adult life when the cornea regenerates after injury. The common reaction of the cornea to injury is the formation of opaque scars, the ingrowth of blood vessels, and distinct changes in the innervation pattern. Scar formation of the cornea is critically modulated by the expression of transforming growth factor-beta (TGF-beta). To identify genes that are important for corneal transparency, dense innervation and absence of blood vessels by comparing corneas from wildtype mice with those that are under the influence of high doses of TGF-beta. Transparency, dense innervation, and absence of blood vessels in the cornea all depend on the expression of a critical set of genes that are not expressed when TGF-beta is present. Mice were generated that overexpress TGF-beta under control of a strong lens-specific promoter. These mice developed opaque corneas that are vascularized and lack sensory nerves. In addition, these corneas were densely populated with cells expressing neural cell adhesion protein. RNA was isolated from corneas of transgenic animals and wildtype littermates in order to analyze differentially expressed genes and to identify those that are only expressed in transparent, avascular, and densely innervated wildtype corneas.

ORGANISM(S): Mus musculus

SUBMITTER: Elizabeth Salomon

PROVIDER: E-GEOD-6676 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The cornea is the transparent tissue covering the anterior part of the eye. Its main roles are to convey the light toward the retina, and to act as a protective barrier against infection or injury for the eye. The transparency of the cornea is a crucial component of its functionality and is the result of specific architecture and cell arrangements. The inner layer of the cornea is the endothelium, composed of a monolayer of endothelial cells. The next layer is the stroma, representing about two third of the thickness of the cornea, and is mainly composed of a specifically arranged extracellular matrix, secreted by few keratocytes1â€“4. Finally, the external layer is a life-long renewed pluristratified epithelium. The regulated epithelial homeostasis, crucial to maintain the corneal transparency, relies on stem and progenitor cells5. To coordinate epithelial homeostasis and healing, and to adequately respond to any change in the corneal environment, this tissue is highly innervated6,7. The corneal innervation is mainly composed of A and C sensory fibres whose cell bodies are located in the ophthalmic branch of the trigeminal ganglion8. Those fibres penetrate the corneal stroma from the periphery, as bundles of fibres branching and spreading within the stroma9. When entering in the epithelium, the fibres branche again and radiate horizontally to form the subbasal plexus. Finally, the sensory fibres shift orientation to reach the top of the epithelium, where they end up as free nerve endings6,7. There are three classes of fibres innervating the cornea: the mechano-nociceptors, the cold sensing neurons and the polymodal nociceptors, reacting respectively to mechanical, thermal and chemical stimuli10,11. Stimuli transduction is not the only role of the corneal innervation, as these fibres have a crucial role on epithelial homeostasis through the secretion of trophic factors essential for epithelial cell survival12. Due to its localization, the cornea is highly exposed to ultraviolet radiation and high oxygen tension, making it particularly vulnerable to mitochondrial defects13. These defects can be either inherited or non-inherited. Inherited forms result from mutations in mitochondrial DNA (mtDNA) or nuclear gene defects affecting mitochondrial function14. Inherited mitochondrial dysfunction is a key factor in the progression of Fuchs endothelial corneal dystrophy (FECD) and keratoconus13,15,16. Non-inherited mitochondrial dysfunction, on the other hand, can occur due to spontaneous mtDNA mutations or somatic mutations that accumulate with age, rendering the mitochondrial metabolism less efficient with time17. To date, the impact of inherited mitochondrial dysfunctions on corneal epithelium physiology has not been extensively studied. Case reports have linked mitochondrial diseases to corneal cloudiness18,19, perforation20 and edema21. Furthermore, mitochondrial defect was associated to inflammatory context and ROS production in ocular surface pathologies13,22. Despite these studies, the direct effect of mitochondrial disfunction on corneal biology remains elusive. Among the known pathologies originating from an inherited mitochondrial dysfunction, the dominant optic atrophy (DOA) is an inherited blinding disease caused by the degenescence of the retinal cell ganglions forming the optic nerve23. The mutation of the gene OPA1 is responsible for the majority of the DOA diagnostics. OPA1 gene encodes for a mitochondrial protein involved in the fusion process and is essential to maintain the organelle integrity. Generally, optic neuropathy is the characteristic syndrome for DOA, but a subset of patients, called dominant optic atrophy plus (DOA+), also declare extra-ocular syndromes such as ataxia, deafness and peripheral neuropathies24,25. A mouse model, bearing the OPA1delTTAG mutation, recapitulates the degenerative syndromes encountered in DOA+ patients25.. While DOA is associated with lens cloudiness, no report has linked DOA to ocular surface defects. Here, we investigated the impact of OPA1 delTTAG mutation on mouse cornea as its structure includes a large amout of sensory fibres that are crucial to maintain corneal homeostasis.

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Transcription profiling of mouse corneas from wildtype vs. corneas under the influence of high doses of TGF-beta

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