Current Molecular Medicine (v.10, #9)

Some years ago, I attended a research conference on the macular degeneration in the John Hopkins Medical Center where I obtained a set of textbooks named and#x2018;Principles and Practice of Ophthalmology (second edition)and#x2019; by Daniel A. Albert and Frederick A. Jakobiec. Of 6 volumes, the longest one deals with the basic sciences of ophthalmology, which contains over 1400 pages in 119 chapters by over 150 authors. If you have read this textbook and are invited to edit a special issue about molecular ophthalmology with just a few articles, you may wonder what to do with such extensive topics as I did in the beginning. Nevertheless, the eye is a beautiful organ and ocular diseases greatly affect our health. Thus, this special edition of Current Molecular Medicine contains the review articles on the pathology, the related mechanism and the possible management of the major ocular diseases. Seven articles have been selected to cover retinal pigment epithelium and retinal diseases, glaucoma and treatment, cataractogenesis derived from changes in lens structural proteins, gap junctions or cell death, and corneal disease therapy by limbal stem cells. The small heat shock proteins (sHsps) have extremely important roles in the eye. Among the 11 different sHsps, and#945;A/B-crystallins are lens structural proteins. These two and also Hsp27 are expressed in three major compartments (retina, lens and cornea) of the eye where they perform both structural and non-structural roles. The article by Arrigo and Simon reviewed the functions of these sHsps in the eye. After a brief discussion on their developmental expression, the authors gave a detailed description of these sHsps in acting as chaperones, anti-oxidative components and anti-apoptotic regulators. Then, the authors discussed various mutations and functional changes of the three major sHsps that lead to cataractogenesis, corneal and retinal pathogenesis. Finally, the authors suggested the potential using sHsps for ocular disease therapy. This is one of the most comprehensive reviews about the roles of sHsps in ocular diseases. SUMOylation is a post-translation process in which various substrate proteins such as transcriptional factors and signaling molecules are modified by addition of a single SUMO peptide (SUMO 1) or multiple copies of SUMO peptides (2 and 3). The discovery of this posttranslational modification came to the stage about a decade ago. The article by Gong and Li provided an updated review regarding the functions of SUMOylation in the eye. SUMOylation plays a very important role in regulating the differentiation of both retina and lens. In this article, the authors summarized the functions of SUMOylation in modulating two important transcription factors, Nr2e3 and Nrl, which regulate differentiation of rods and cones in the retina. They further discussed the function modification of the p32 Pax-6 by SUMOylation, which turns on both DNA binding and transcription activation. Finally, the authors discussed the modification of the surviving factor, Ledgf, by SUMOylation and the possible role of this modification. Photo-transduction is the major functional process of the eye. During this process, the retinal pigment epithelium plays an indispensable role. The article by Sparrow et al. provided an updated review about the retinal pigment epithelium in normal health and diseases. The author first described the structural features of the retinal pigment epithelial cells (RPE), and its functional importance related to photo-transduction by the photoreceptor cells (PR). Then, the author discussed the major functions of RPE in conversion and storage of retinoid, the phagocytosis of shed PR outer segment membrane, the absorption of scattered light, ion and fluid transport and RPE-PR apposition, and the primary dysfunctioning of the RPE in visual cell death and blindness. Glaucoma is a syndrome derived from optic nerve damage, and progressive and irreversible loss of vision, which is likely due to increased intraocular pressure. The article by Toris reviewed the basis for this disease and also its treatment. The author first discussed the aqueous humor dynamics, which determines the intraocular pressure. Then, the author described the three types of drugs used for glaucoma treatment: those suppressing aqueous facility, those enhancing aqueous facility and those having both suppressing and enhancing effects, and provided an updated review on glaucoma therapy by these different drugs. A transparent cornea is essential for reflecting light into the eye. The article by Tseng et al. discussed how to use the limbal epithelial stem cells for treatment of human corneal diseases. After a brief recall of the historical background regarding limbal epithelial stem cell study, the authors gave a critical appraisal about the current protocols used for ex vivo expansion of human limbal epithelial cells and indicated the potential pitfalls in each of the six protocols. The authors finally concluded that the major aspect one can improve regarding ex vivo expansion of human limbal epithelial cells is how to develop the surrogate feeder layers more like the native limbal niche environment. Gap junctions are important membrane channels mediating direct cell-cell communication in multicellular organisms. The article by Jiang et al. provided a comprehensive review about the hemi-channels and gap junctions derived from two types of junction proteins: Cx46 and Cx50 in the ocular lens. The author first described their expression in lens fiber cells, the various types of mutations across different domains of connexin molecules and the genetic deletion of the two genes related to development of cataracts. The author further discussed the differential functions of Cx46 and Cx50 in lens cell growth and development and suggested that the function of Cx50 in epithelial-fiber differentiation appears to be derived from its non-conventional role. Finally, the author suggested that connexin molecules might be potential drug targets for therapeutic intervention for the treatment of cataracts and other eye disorders. Lens cataract is derived from genetic mutations (congenital cataract), aging or lens damage induced by various stress conditions (non-congenital cataract). The article by Zhang et al. summarized the current knowledge about the functions of both developmental apoptosis in the embryonic lens and stress-induced apoptosis in the adult lens, and discussed the close relationships between induced apoptosis and microphthalmia and/or cataractogenesis. The authors also reviewed the major regulators controlling apoptosis in the ocular lens. In summary, this special issue touches aspects of the comprehensive vision science field. It is our intention to give the readers both a general overview on the topic selected and also specific advance in that field covered. ACKNOWLEDGEMENTS I thank the financial support from the National Eye Institute/ National Institutes of Health (EY018380 and EY015765) and other organizations including the University of Nebraska Medical Center, the University of Minnesota Graduate School, the New Jersey Foundation, and the Lotus Scholar Program from the Ministry of Hunan Province Government and Hunan Normal University.

Heat shock proteins (Hsps) are expressed in mammalian embryonic, adult and aging lens, cornea and retina. These proteins, particularly those belonging to the family of small Hsps, such as and#945;A-crystallin (HspB4) and and#946;B-crystallin (HspB5), play important roles in the differentiation of lens cells and are essential for the maintenance and protection of the supraorganization of proteins in differentiated corneal and lens fiber cells. Hsps are molecular chaperones characterized by their protective activity against different types of stress. They also have anti-apoptotic and anti-oxidant functions that help lens and corneal cells to better cope with the oxidative conditions that result from light induced injuries. They are also effective to protect the retina against the high rate of oxidative metabolism observed in this tissue. The goal of this review is to highlight recent works describing the expression and function(s) of the different Hsps as an attempt to better understand their roles in the normal and pathological eye. Particular emphasis is given to the and#945;-crystallin polypeptides which, in addition to their protective functions, are key structural polypeptides that are essential for the refractive and light focusing properties of the lens, a property demonstrated by the caractogenic potential of their mutations.

SUMOylation in Ocular Development and Pathology by L. Gong, D. W.-C. Li (794-801).
SUMOylation, a posttranslational modification process in which SUMO, the small ubiquitin-related modifier or small ubiquitin-like modifier, is added to the target proteins, plays an important role in regulating a variety of cellular processes including protein-protein interactions, subcellular localization, protein-DNA interactions and enzyme activity. This process adds another layer of control in eukaryote gene expression, and it regulates both transcriptional activation and repression. In the present review, we summarized the currently emerging information regarding the function of SUMOylation in ocular development and pathology.

The Retinal Pigment Epithelium in Health and Disease by J. R. Sparrrow, D. Hicks, C. P. Hamel (802-823).
Retinal pigment epithelial cells (RPE) constitute a simple layer of cuboidal cells that are strategically situated behind the photoreceptor (PR) cells. The inconspicuousness of this monolayer contrasts sharply with its importance [1]. The relationship between the RPE and PR cells is crucial to sight; this is evident from basic and clinical studies demonstrating that primary dysfunctioning of the RPE can result in visual cell death and blindness. RPE cells carry out many functions including the conversion and storage of retinoid, the phagocytosis of shed PR outer segment membrane, the absorption of scattered light, ion and fluid transport and RPE-PR apposition. The magnitude of the demands imposed on this single layer of cells in order to execute these tasks, will become apparent to the reader of this review as will the number of clinical disorders that take origin from these cells.

Pharmacotherapies for Glaucoma by C. B. Toris (824-840).
Glaucoma is a group of progressive optic neuropathies in which the axons in the optic nerve are injured, retinal ganglion cell numbers are reduced and vision is gradually and permanently lost. The only approved and effective way to treat glaucoma is to reduce the intraocular pressure (IOP). This is usually accomplished by surgical and/or pharmacological means. Drugs designed to reduce IOP target one or more of the parameters that maintain it. These parameters (collectively known as aqueous humor dynamics) are the production rate of aqueous humor, the pressure in the episcleral veins and the drainage of aqueous humor through the trabecular or uveoscleral outflow pathways. Intraocular pressure lowering drugs can be classified as inflow or outflow drugs depending on whether they reduce aqueous humor inflow into the anterior chamber or improve aqueous humor outflow from the anterior chamber. Inflow drugs, like and#946;adrenergic antagonists and carbonic anhydrase inhibitors, reduce the rate of aqueous humor production. Outflow drugs, like prostaglandin analogs, cholinergic agonists and sympathomimetics, increase the rate of drainage through the uveoscleral outflow pathway and/or increase the facility of outflow through the trabecular meshwork. Some drugs have mixed inflow/outflow effects. This review summarizes the pharmacological treatments for glaucoma in use today and some new drugs showing potential for use in the future.

Critical Appraisal of Ex Vivo Expansion of Human Limbal Epithelial Stem Cells by S. C.G. Tseng, S.-Y. Chen, Y.-C. Shen, W.-L. Chen, F.-R. Hu (841-850).
The stem cells (SCs) of the corneal epithelium located in the limbal basal layer are the ultimate source to maintain corneal epithelial homeostasis. Like other adult tissue-specfic SCs, self renewal and fate decision of limbal SCs are regulated by a specialized in vivo microenvironment, termed and#x201C;nicheand#x201D;. Loss of limbal SCs or dysfunction of the limbal niche renders corneas with a unique clinical disease labeled limbal stem cell deficiency (LSCD). Besides transplantation of autologous or allogeneic limbal SCs or amniotic membrane, a new strategy of treating LSCD is to transplant a bio-engineered graft by expanding limbal SCs ex vivo. Herein, we conduct a critical appraisal of six protocols that have successfully been practiced in treating human patients with LSCD, and identify issues whether niche regulation has been disrupted or maintained during isolation and expansion. Consequently, we propose a future direction that may circumvent the potential pitfalls existing in these conventional protocols by preserving the interaction between limbal SCs and their native niche cells during isolation and expansion. Such an approach may one day help realize considerable promise held by adult SCs in treating a number of diseases.

In the last decade or so, increasing evidences suggest that the mutations of two connexin genes, GJA3 and GJA8, are directly linked to human congenital cataracts in North and Central America, Europe and Asia. GIA3 and GIA8 genes encode gap junction-forming proteins, connexin (Cx) 46 and Cx50, respectively. These two connexins are predominantly expressed in lens fiber cells. Majority of identified mutations are missense, and the mutated sites are scattered across various domains of connexin molecules. Genetic deletion of either of these two genes leads to the development of cataracts; however, the types of cataracts developed are distinctive. More interestingly, microphthalmia is only developed in Cx50, but not Cx46 deficient mice, suggesting the unique role of Cx50 in lens cell growth and development. Knockin studies with the replacement of Cx46 or Cx50 at their respective gene locus further demonstrate the unique properties of these two connexins. Furthermore, the function of Cx50 in epithelial-fiber differentiation appears to be independent of its conventional role in forming gap junction junction channels. Due to their specific functions in maintaining lens clarity and development, and their malfunctions resulting in lens cataractogenesis and developmental impairment, connexin molecules could be developed as potential drug targets for therapeutic intervention for treatment of cataracts and other eye disorders. Recent advances in basic research of lens connexins and the discoveries of clinical disorders as a result of lens connexin dysfunctions are summarized and discussed here.

Apoptosis: Its Functions and Control in the Ocular Lens by L. Zhang, Q. Yan, J.-P. Liu, L.-J. Zou, J. Liu, S. Sun, M. Deng, L. Gong, W.-K. Ji, D. W.-C. Li (864-875).
The ocular lens is a non-vascular and non-innervated transparent organ that plays an important role in vision processing. This unique organ is derived from the embryonic ectoderm of the brain region through a complicated differentiation process in which apoptosis plays a key role. First, when the committed ectoderm becomes thickened and invaginated, the defined number of cells required to form the lens vesicle is partially determined by apoptosis. Second, separation of lens vesicle from the above corneal ectoderm is executed through apoptosis of the lens stalk cells. Finally, differentiation of the lens epithelial cells is controlled by the regulators, most of which are involved in control of apoptosis at multiple signaling steps. The lens is also characterized by continuous growth and differentiation in the adulthood. Through the different stages of growth and differentiation in the adult lens, various stress conditions can induce apoptosis of the lens epithelial cells, leading to eventual non-congenital cataractogenesis. The present review summarizes the current knowledge on the functions and regulators of apoptosis in the ocular lens.