I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

Located between vessels of the choriocapillaris and light-sensitive outer segments of the photoreceptors, the retinal pigment epithelium (RPE) closely interacts with photoreceptors in the maintenance of visual function. Increasing knowledge of the multiple functions performed by the RPE improved the understanding of many diseases leading to blindness. This review summarizes the current knowledge of RPE functions and describes how failure of these functions causes loss of visual function. Mutations in genes that are expressed in the RPE can lead to photoreceptor degeneration. On the other hand, mutations in genes expressed in photoreceptors can lead to degenerations of the RPE. Thus both tissues can be regarded as a functional unit where both interacting partners depend on each other.

The Retinal Pigment Epithelium in Visual Function

A fundamental function of epithelia and endothelia is to separate different compartments within the organism and to regulate the exchange of substances between them. The tight junction (TJ) constitutes the barrier both to the passage of ions and molecules through the paracellular pathway and to the movement of proteins and lipids between the apical and the basolateral domains of the plasma membrane. In recent years more than 40 different proteins have been discovered to be located at the TJs of epithelia, endothelia and myelinated cells. This unprecedented expansion of information has changed our view of TJs from merely a paracellular barrier to a complex structure involved in signaling cascades that control cell growth and differentiation. Both cortical and transmembrane proteins integrate TJs. Among the former are scaffolding proteins containing PDZ domains, tumor suppressors, transcription factors and proteins involved in vesicle transport. To date two components of the TJ filaments have been identified: occludin and claudin. The latter is a protein family with more than 20 members. Both occludin and claudins are integral proteins capable of interacting adhesively with complementary molecules on adjacent cells and of co-polymerizing laterally. These advancements in the knowledge of the molecular structure of TJ support previous physiological models that exhibited TJ as dynamic structures that present distinct permeability and morphological characteristics in different tissues and in response to changing natural, pathological or experimental conditions.

Tight junction proteins.

Claudins are tight junction membrane proteins that are expressed in epithelia and endothelia and form paracellular barriers and pores that determine tight junction permeability. This review summarizes our current knowledge of this large protein family and discusses recent advances in our understanding of their structure and physiological functions.

Claudins and the Modulation of Tight Junction Permeability

Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions.

Integration of tight junctions and claudins with the barrier functions of the retinal pigment epithelium.

Purpose.
The retinal pigment epithelium (RPE) separates photoreceptors from choroidal capillaries, but in age-related macular degeneration (AMD) capillaries breach the RPE barrier. Little is known about human RPE tight junctions or the effects of serum on the retinal side of the RPE.

Claudin-19 and the Barrier Properties of the Human Retinal Pigment Epithelium

PURPOSE. Bevacizumab and ranibizumab are currently used to treat age-related macular degeneration by neutralizing vascular endothelial growth factor (VEGF). In this study, the potential side effects on the outer blood–retinal barrier were examined. METHODS. Human fetal RPE (hfRPE) cells were used because they are highly differentiated in culture. The claudin composition of RPE tight junctions was determined by RT-PCR, immunoblot analysis, and immunofluorescence. ELISA assays monitored the secretion and trafficking of VEGF and a fluid-phase marker, methylpolyethylene glycol (mPEG). Tight junction functions were assessed by the conductance of K and Na (derived from the transepithelial electrical resistance, TER) and the flux of NaCl and mPEG. RESULTS. Claudin-3, claudin-10, and claudin-19 were detected in RPE tight junctions. VEGF was secreted in equal amounts across the apical and basolateral membranes, but the apical membrane was more active in endocytosing and degrading VEGF. Exogenous VEGF and mPEG crossed the RPE monolayer by transcytosis, predominantly in the apical-to-basal direction. RPE tight junctions were selective for K, but did not discriminate between Na and Cl. VEGF, bevacizumab, and ranibizumab had minimal effects on TER, permeation of mPEG, and selectivity for K ,N a, and Cl. They had minimal effects on the expression and distribution of the claudins. CONCLUSIONS. RPE has mechanisms for maintaining low concentrations of VEGF in the subretinal space that include endocytosis and degradation and fluid-phase transcytosis in the apicalto-basal direction. RPE tight junctions are selective for K over Na and Cl. Permeability and selectivity of the junctions are not affected by VEGF, bevacizumab, or ranibizumab. (Invest Ophthalmol Vis Sci. 2010;51:3216 –3225) DOI:10.1167/ iovs.09-4162

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Minimal Effects of VEGF and Anti-VEGF Drugs on the Permeability or Selectivity of RPE Tight Junctions

of its apical surface interdigitate with the outer segments of photoreceptors, whereas its highly infolded basal membrane interacts with Bruch’s membrane, serum components that cross the fenestrated choriocapillaris, and the secretions of the various choroidal cell types. The effect of the RPE on the properties of the neighboring cells is well documented, but the effects of neighboring environments on the RPE are less well studied. 2– 6 During pathogenesis, these environments can change. The accumulation of drusen in Bruch’s membrane may alter basal interactions, whereas a break in the RPE monolayer would allow serum to reach the apical surface of the epithelium. Culture studies suggest that subretinal serum further degrades the RPE barrier. 7,8 A defining characteristic of simple, transporting epithelia is the circumferential band of tight junctions that seal the space between neighboring cells of the monolayer. 9 Tight junctions are semiselective in their ability to retard the transepithelial diffusion of solutes across these paracellular spaces. Furthermore, the permeability and selectivity of the junctions can be regulated physiologically and pharmacologically. During embryogenesis, the tight junctions of RPE cells become progressively less permeable, and there are changes in selectivity. 10,11 The process is regulated by the developing neural retina and

Apical and basal regulation of the permeability of the retinal pigment epithelium.

A culture model has been established to study the gradual development of tight junctions during the embryogenesis of the chick retinal pigment epithelium. This study asks how closely the culture model reflects normal development and how the composition, structure and function of embryonic tight junctions are affected by the apical and basal environments. The study focused on the expression of claudins, the fine-structure of tight junctional strands and the transepithelial electrical resistance. Between embryonic days 7 and 14, patches of junctional strands gradually expanded and coalesced to form a continuous junction, in vivo. Although there was a corresponding increase in claudin expression, different claudins appeared at different times. In culture, the apical and basal environments acted synergistically to promote a continuous network of tight junctions with higher electrical resistance. Independently, pituitary extract or the secretory products of either embryonic fibroblasts or the retina promoted the formation of tight junctions. In combination, three effects were identified. With basally placed fibroblast conditioned medium, apical retinal medium increased transepithelial electrical resistance by affecting structure alone. With basally placed pituitary extract, apical retinal conditioned medium increased transepithelial electrical resistance by affecting structure and by modulating claudin expression in a manner that was consistent with development in vivo. Although embryonic day 7 and 14 cultures in retinal medium exhibited similar structure, the transepithelial electrical resistance of the embryonic day 14 cultures was higher. This higher transepithelial electrical resistance correlated with differences in claudin expression and localization. Therefore, this experimental model can isolate the effects of retinal secretions on structure and claudin expression, and can help us to determine how claudins affect function when structure is held constant.

Shaomin Peng

Papers

Integration of tight junctions and claudins with the barrier functions of the retinal pigment epithelium.

Claudin-19 and the Barrier Properties of the Human Retinal Pigment Epithelium

Minimal Effects of VEGF and Anti-VEGF Drugs on the Permeability or Selectivity of RPE Tight Junctions

Apical and basal regulation of the permeability of the retinal pigment epithelium.

The apical and basal environments of the retinal pigment epithelium regulate the maturation of tight junctions during development