The Blood-Retina Barrier

The blood-retina barrier (BRB) is composed of both an inner and an outer barrier. The outer BRB refers to the barrier formed at the retinal pigment epithelial (RPE) cell layer and functions, in part, to regulate the movement of solutes and nutrients from the choroid to the sub-retinal space. In contrast, the inner BRB, similar to the blood brain barrier (BBB) is located in the inner retinal microvasculature and comprises the microvascular endothelium which line these vessels. The tight junctions located between these cells mediate highly selective diffusion of molecules from the blood to the retina and the barrier is essential in maintaining retinal homeostasis. In this chapter, we summarize the key differences between the iBRB and oBRB and outline the molecular constituents of the tight junctions associated with the iBRB. We also describe a process for modulation of the iBRB to enhance systemic delivery of therapeutics to the retina, a technology which may pave the way for safer and more effective therapies for retinal diseases.

[1]  T. Inai,et al.  Claudin-1 contributes to the epithelial barrier function in MDCK cells. , 1999, European journal of cell biology.

[2]  L. González-Mariscal,et al.  Nuclear localization of the tight junction protein ZO-2 in epithelial cells. , 2002, Experimental cell research.

[3]  P. J. Kausalya,et al.  Connexin45 directly binds to ZO‐1 and localizes to the tight junction region in epithelial MDCK cells , 2001, FEBS letters.

[4]  P. Campochiaro,et al.  Localization of blood-retinal barrier breakdown in human pathologic specimens by immunohistochemical staining for albumin. , 1990, Laboratory investigation; a journal of technical methods and pathology.

[5]  T. Noda,et al.  Occludin-deficient Embryonic Stem Cells Can Differentiate into Polarized Epithelial Cells Bearing Tight Junctions , 1998, The Journal of cell biology.

[6]  J. Cunha-Vaz,et al.  Iatrogenic choroidal neovascularization in sickle cell retinopathy. , 1986, Ophthalmology.

[7]  A. Zahraoui.  [Tight junctions, a platform regulating cell proliferation and polarity]. , 2004, Medecine sciences : M/S.

[8]  E. Dejana,et al.  Homophilic Interaction of Junctional Adhesion Molecule* , 2000, The Journal of Biological Chemistry.

[9]  Alan W. Stitt,et al.  Endostatin modulates VEGF-mediated barrier dysfunction in the retinal microvascular endothelium. , 2005, Experimental eye research.

[10]  L. Gu,et al.  ZO-3, a Novel Member of the MAGUK Protein Family Found at the Tight Junction, Interacts with ZO-1 and Occludin , 1998, The Journal of cell biology.

[11]  H. Dorchy.  Characterization of Early Stages of Diabetic Retinopathy: Importance of the Breakdown of the Blood-Retinal Barrier , 1993, Diabetes Care.

[12]  M. Itoh,et al.  Expression and distribution of ZO‐3, a tight junction MAGUK protein, in mouse tissues , 2003, Genes to cells : devoted to molecular & cellular mechanisms.

[13]  A. Kennan,et al.  Aberrant retinal tight junction and adherens junction protein expression in an animal model of autosomal recessive Retinitis pigmentosa: The Rho(−/−) mouse , 2006 .

[14]  Erika S Wittchen,et al.  Protein Interactions at the Tight Junction , 1999, The Journal of Biological Chemistry.

[15]  T. Galli,et al.  Tight Junction, a Platform for Trafficking and Signaling Protein Complexes , 2000, The Journal of cell biology.

[16]  Karl Matter,et al.  The tight junction protein ZO‐1 and an interacting transcription factor regulate ErbB‐2 expression , 2000, The EMBO journal.

[17]  S. Baker,et al.  Oxidant-induced disruption of intestinal epithelial barrier function: role of protein tyrosine phosphorylation. , 1997, American journal of physiology. Gastrointestinal and liver physiology.

[18]  E. López-Bayghen,et al.  The tight junction protein ZO-2 associates with Jun, Fos and C/EBP transcription factors in epithelial cells. , 2004, Experimental cell research.

[19]  P. Muriel,et al.  Tight junction proteins ZO-1, ZO-2, and occludin along isolated renal tubules. , 2000, Kidney international.

[20]  D. Fong,et al.  VISUAL SIDE EFFECTS OF SUCCESSFUL SCATTER LASER PHOTOCOAGULATION SURGERY FOR PROLIFERATIVE DIABETIC RETINOPATHY: A Literature Review , 2007, Retina.

[21]  M. Garrett,et al.  The ZO-1–associated Y-box factor ZONAB regulates epithelial cell proliferation and cell density , 2003, The Journal of cell biology.

[22]  R. D. Lynch,et al.  Occludin is a functional component of the tight junction. , 1996, Journal of cell science.

[23]  M. Arpin,et al.  The junction-associated protein, zonula occludens-1, localizes to the nucleus before the maturation and during the remodeling of cell-cell contacts. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[24]  F. Orsenigo,et al.  Interaction of Junctional Adhesion Molecule with the Tight Junction Components ZO-1, Cingulin, and Occludin* , 2000, The Journal of Biological Chemistry.

[25]  P. Bryant,et al.  ZO-1, DlgA and PSD-95/SAP90: homologous proteins in tight, septate and synaptic cell junctions , 1993, Mechanisms of Development.

[26]  M. Itoh,et al.  Occludin: a novel integral membrane protein localizing at tight junctions , 1993, The Journal of cell biology.

[27]  Elisabetta Dejana,et al.  Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. , 2004, Physiological reviews.

[28]  Kathleen A. Marshall,et al.  Safety and efficacy of gene transfer for Leber's congenital amaurosis. , 2008, The New England journal of medicine.

[29]  L. Rubin,et al.  p120, a p120-related protein (p100), and the cadherin/catenin complex , 1995, The Journal of cell biology.

[30]  J. Anderson,et al.  PDZ domains and the formation of protein networks at the plasma membrane. , 1998, Current topics in microbiology and immunology.

[31]  S. Resnikoff,et al.  Global data on visual impairment in the year 2002. , 2004, Bulletin of the World Health Organization.

[32]  Ahmed Zahraoui.  Les jonctions serrées : Plate-forme de régulation de la prolifération et de la polarité cellulaires , 2004 .

[33]  T. Gardner,et al.  Vascular Endothelial Growth Factor Induces Rapid Phosphorylation of Tight Junction Proteins Occludin and Zonula Occluden 1 , 1999, The Journal of Biological Chemistry.

[34]  S. Citi,et al.  Evidence for a Functional Interaction between Cingulin and ZO-1 in Cultured Cells* , 2002, The Journal of Biological Chemistry.

[35]  B. Rothen‐Rutishauser,et al.  A ZO1-GFP fusion protein to study the dynamics of tight junctions in living cells , 2002, Histochemistry and Cell Biology.

[36]  M. Saitou,et al.  Possible Involvement of Phosphorylation of Occludin in Tight Junction Formation , 1997, The Journal of cell biology.

[37]  T. Freddo.  Intercellular junctions of the iris epithelia in Macaca mulatta. , 1984, Investigative ophthalmology & visual science.

[38]  M. Ryan,et al.  Occludin: structure, function and regulation. , 2005, Advanced drug delivery reviews.

[39]  K. Fujimoto,et al.  A Single Gene Product, Claudin-1 or -2, Reconstitutes Tight Junction Strands and Recruits Occludin in Fibroblasts , 1998, The Journal of cell biology.

[40]  Finnian Hanrahan,et al.  Systemic low-molecular weight drug delivery to pre-selected neuronal regions , 2011, EMBO molecular medicine.

[41]  A. Ávila-Flores,et al.  MAGUK proteins: structure and role in the tight junction. , 2000, Seminars in cell & developmental biology.

[42]  M. Itoh,et al.  Characterization of ZO-2 as a MAGUK Family Member Associated with Tight as well as Adherens Junctions with a Binding Affinity to Occludin and α Catenin* , 1999, The Journal of Biological Chemistry.

[43]  P. Humphries,et al.  Altered expression and interaction of adherens junction proteins in the developing OLM of the Rho(-/-) mouse. , 2007, Experimental eye research.

[44]  W. Hauswirth,et al.  Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. , 2008, Human gene therapy.

[45]  B. Giepmans,et al.  The gap junction protein connexin43 interacts with the second PDZ domain of the zona occludens-1 protein , 1998, Current Biology.

[46]  James M. Anderson,et al.  Two classes of tight junctions are revealed by ZO-1 isoforms. , 1993, The American journal of physiology.

[47]  M. Itoh,et al.  Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions , 1994, The Journal of cell biology.

[48]  B. Olsen,et al.  Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. , 2005, The American journal of pathology.

[49]  P. Nava,et al.  Tight junction proteins. , 2003, Progress in biophysics and molecular biology.

[50]  P. Bryant,et al.  Loss of the tight junction MAGUK ZO-1 in breast cancer: relationship to glandular differentiation and loss of heterozygosity. , 1998, The American journal of pathology.

[51]  Glenn J Jaffe,et al.  Ranibizumab and bevacizumab for neovascular age-related macular degeneration. , 2011, The New England journal of medicine.

[52]  S. Tsukita,et al.  Size-selective loosening of the blood-brain barrier in claudin-5–deficient mice , 2003, The Journal of cell biology.

[53]  R. Rao,et al.  Tyrosine phosphorylation of occludin attenuates its interactions with ZO-1, ZO-2, and ZO-3. , 2003, Biochemical and biophysical research communications.

[54]  Nick Tyler,et al.  Effect of gene therapy on visual function in Leber's congenital amaurosis. , 2008, The New England journal of medicine.

[55]  G. Palade,et al.  JUNCTIONAL COMPLEXES IN VARIOUS EPITHELIA , 1963, The Journal of cell biology.

[56]  M. Itoh,et al.  Involvement of ZO-1 in Cadherin-based Cell Adhesion through Its Direct Binding to α Catenin and Actin Filaments , 1997, The Journal of cell biology.

[57]  Kazushi Fujimoto,et al.  Claudin-1 and -2: Novel Integral Membrane Proteins Localizing at Tight Junctions with No Sequence Similarity to Occludin , 1998, The Journal of cell biology.

[58]  Alan W. Stitt,et al.  Involvement of MAPKs in Endostatin-Mediated Regulation of Blood-Retinal Barrier Function , 2006, Current eye research.

[59]  B. Wiesner,et al.  Formation of tight junction: determinants of homophilic interaction between classic claudins , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[60]  W R Green,et al.  Blood-retinal barrier breakdown in retinitis pigmentosa: light and electron microscopic immunolocalization. , 1995, Histology and histopathology.

[61]  P. Humphries,et al.  RNAi‐mediated reversible opening of the blood‐brain barrier , 2008, The journal of gene medicine.

[62]  P. Humphries,et al.  An experimental platform for systemic drug delivery to the retina , 2009, Proceedings of the National Academy of Sciences.

[63]  E. Segre,et al.  ADRENAL SUPPRESSION BY CLOBETASOL PROPIONATE , 1975, The Lancet.

[64]  W. Pardridge.  Molecular Trojan horses for blood-brain barrier drug delivery. , 2006, Discovery medicine.

[65]  B. Shin,et al.  Colocalization of tight junction proteins, occludin and ZO-1, and glucose transporter GLUT1 in cells of the blood-ocular barrier in the mouse eye , 1998, Histochemistry and Cell Biology.

[66]  Anand Swaroop,et al.  Unraveling a multifactorial late-onset disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration. , 2009, Annual review of genomics and human genetics.

[67]  M. Itoh,et al.  The 220-kD protein colocalizing with cadherins in non-epithelial cells is identical to ZO-1, a tight junction-associated protein in epithelial cells: cDNA cloning and immunoelectron microscopy , 1993, The Journal of cell biology.

[68]  K. Foust,et al.  Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes , 2009, Nature Biotechnology.

[69]  G. Bazzoni.  The JAM family of junctional adhesion molecules. , 2003, Current opinion in cell biology.

[70]  S. Schreiber,et al.  Structure-function analysis of SH3 domains: SH3 binding specificity altered by single amino acid substitutions , 1995, Molecular and cellular biology.

[71]  James M. Anderson,et al.  Connexin-Occludin Chimeras Containing the Zo-Binding Domain of Occludin Localize at Mdck Tight Junctions and Nrk Cell Contacts , 1999, Journal of Cell Biology.

[72]  R. Masland.  The fundamental plan of the retina , 2001, Nature Neuroscience.

[73]  J. Siliciano,et al.  Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia , 1986, The Journal of cell biology.

[74]  E. López-Bayghen,et al.  Characterization of the tight junction protein ZO-2 localized at the nucleus of epithelial cells. , 2004, Experimental cell research.

[75]  E. Rodriguez-Boulan,et al.  Morphogenesis of the Retinal Pigment Epithelium: Toward Understanding Retinal Degenerative Diseases a , 1998, Annals of the New York Academy of Sciences.

[76]  T. Gardner,et al.  Molecular mechanisms of vascular permeability in diabetic retinopathy. , 1999, Seminars in ophthalmology.

[77]  V. Wong.  Phosphorylation of occludin correlates with occludin localization and function at the tight junction. , 1997, American journal of physiology. Cell physiology.