|Year : 2015 | Volume
| Issue : 3 | Page : 329-339
Extracellular Matrix components regulate cellular polarity and tissue structure in the developing and mature Retina
Shweta Varshney PhD 1, Dale D Hunter PhD; JD 2, William J Brunken PhD 2
1 Department of Ophthalmology and Cell Biology, SUNY Downstate Medical Center, Brooklyn NY; SUNY Eye Institute, NY, USA
2 Department of Ophthalmology and Cell Biology, SUNY Downstate Medical Center; SUNY Eye Institute; Department of Ophthalmology and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA
|Date of Submission||25-May-2015|
|Date of Acceptance||26-Jun-2015|
|Date of Web Publication||26-Nov-2015|
William J Brunken
Department of Ophthalmology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210
Source of Support: None, Conflict of Interest: None
While genetic networks and other intrinsic mechanisms regulate much of retinal development, interactions with the extracellular environment shape these networks and modify their output. The present review has focused on the role of one family of extracellular matrix molecules and their signaling pathways in retinal development. In addition to their effects on the developing retina, laminins play a role in maintaining Müller cell polarity and compartmentalization, thereby contributing to retinal homeostasis. This article which is intended for the clinical audience, reviews the fundamentals of retinal development, extracellular matrix organization and the role of laminins in retinal development. The role of laminin in cortical development is also briefly discussed.
Keywords: Dystroglycanopathy; Laminin; Müller Cell; Retinal Progenitor Cell
|How to cite this article:|
Varshney S, Hunter DD, Brunken WJ. Extracellular Matrix components regulate cellular polarity and tissue structure in the developing and mature Retina. J Ophthalmic Vis Res 2015;10:329-39
|How to cite this URL:|
Varshney S, Hunter DD, Brunken WJ. Extracellular Matrix components regulate cellular polarity and tissue structure in the developing and mature Retina. J Ophthalmic Vis Res [serial online] 2015 [cited 2020 Apr 8];10:329-39. Available from: http://www.jovr.org/text.asp?2015/10/3/329/170354
| Introduction|| |
Mammalian vision begins with transmission of light through the cornea and lens to the retina. The highly specialized retina converts energy from absorbed photons into neural activity such that the brain can interpret the pattern of the detected photons.
Light energy is transduced into changes in membrane potential in the photoreceptor outer segments, and then into changes in synaptic transmitter output to second order neurons. The retinal network, with complex connectivity among the retinal interneurons, leads to multiple paths of temporally and spatially encoded information about the visual world, including color, motion, size and orientation. This information is transmitted out of the retina by retinal ganglion cells to numerous sites in the brain.
The encoding of light energy into neuronal signaling is produced in the meticulously polarized retina with a defined laminar architecture which underlies its function [Figure 1]. The polarized organization of retinal structure is dependent on appropriate positioning and spacing of cells, as well as proper development of neuronal connections which are required for the generation of functional circuitry. Moreover, retinal homeostasis is dependent on the polarized morphology of Müller cells. The unifying theme in all these processes is establishment and maintenance of cell and tissue polarity.
|Figure 1. Cross s%ectional diagrams of the mammalian retina. All vertebrate retinas are composed of three layers of nerve cell bodies and two layers of synapses. The light transducers, photoreceptors (rods and cones), are positioned outermost in the retina, against the retinal pigment epithelium (rpe) and choroid (not shown). Light is transduced in the outer segments (OS) of rods and cones. The outer nuclear layer (ONL) contains cell bodies of the rods and cones; the inner nuclear layer (INL) contains cell bodies of the bipolar, horizontal and amacrine cells. The output neurons of the retina, ganglion cells, lie in the ganglion cell layer (GCL). Ganglion cell axons course through the nerve fiber layer (NFL) abutting the inner limiting membrane (ILM). In between these cell layers are two synaptic, or plexiform, layers. Synaptic connections between photoreceptors, and bipolar cells and horizontal cells are contained in the outer plexiform layer (OPL) while synapses among bipolar cells, amacrine cells and ganglion cells are found in the inner plexiform layer (IPL). The resident glial cell of the retina, the Müller cell spans nearly the entire thickness of the neural retina. Its end feet adhere to the ILM at the basal surface and it forms adherens junctions with photoreceptors at the apical surface, forming the outer limiting membrane (OLM). Modified with additions from original drawings of Schultze; Ramon y Cajal.|
Click here to view
The seven different types of retinal cells, of which six are neurons and one is a glial cell, the Müller cell (MC), are precisely positioned [Figure 1]., The input neurons (rod and cone photoreceptors) have nuclei in the outer nuclear layer (ONL); the retinal interneurons (horizontal, bipolar and amacrine cells) have nuclei in the inner nuclear layer (INL). A single class of projection neurons, the retinal ganglion cells, is in the eponymous layer, named the retinal ganglion cell layer (GCL). Between these three nuclei and cytoplasm-rich layers, there are nuclei-poor layers in which retinal neurons make synapses, called the outer and inner plexiform layers. The outer plexiform layer (OPL) separates the ONL from the INL and the inner plexiform layer (IPL) separates the INL from the GCL [Figure 1]. A specialized basement membrane, the inner limiting membrane, separates the GCL from the vitreous body and serves as an attachment surface for a variety of retinal cells.
| The Extracellular Matrix and Retinal Basement Membranes|| |
In all metazoans, components of the extracellular matrix (ECM) are organized into thin specialized sheets of basement membranes. The functions of basement membranes are to act as platforms for cell adhesion, to provide structural support to a tissue, to divide tissues into compartments, and to regulate cell behavior including polarity. Polarized cellular functions are regulated by the ECM in a variety of cell types including epithelial cells, neurons,,, immune cells  and glial cells such as astrocytes, oligodendrocytes and Schwann cells.
Interactions of cells with basement membranes are mediated by transmembrane cell surface receptors which connect the cell's cytoskeleton with the extracellular environment, leading to the formation of site-specific focal adhesions., The extracellular cues established by binding of cells to the ECM are propagated to the nucleus from the cell surface by cytoskeletal molecules such as actin and tubulin, resulting in outside-to-inside signaling., Disruptions along this pathway have been reported in both developmental deformities and pathologies in kidney, muscle, skin, central nervous system (CNS), brain and retina.,,,,
The mature, polarized retina is structurally and functionally supported by two basement membranes i.e., Bruch's membrane, at the interface of the retinal pigmented epithelium with the choroid, and the inner limiting membrane (ILM) at the interface of the neural retina with the vitreous body [Figure 1]. Several retinal pathologies result from changes in the organization or composition of these basement membranes. These pathologies include diabetic retinopathy, retinopathy of prematurity, age related macular degeneration and proliferative vitreoretinopathy.,
In the present article, retinal basement membranes will be discussed, including one important class of basement membrane components, the laminins; the interaction of retinal basement membranes with neighboring cells will also be addressed. We will then focus on the role of retinal basement membranes, especially the ILM, in establishing and maintaining cellular polarity within the retina. This polarity is required for the development and function of various retinal cells including retinal progenitor cells, retinal ganglion cells and Müller glial cells. First, the general process of retinal development will be reviewed in this context.
| Retinal Development from a Common Progenitor Cell|| |
The retina arises from an out-pocketing of the diencephalon that projects toward and contacts the surface ectoderm. As the result of interactions between the eye vesicle and the overlying ectoderm (lens placode), the optic vesicle involutes, forming a double-walled eyecup. Each layer of this dual layered eyecup undergoes its own morphological change: The inner layer becomes the neural retina and expands dramatically into a multi-layered structure, while the outer layer, the retinal pigmented epithelium, remains a single cell layer [Figure 2].
|Figure 2. Illustration of eye development from the neural plate. The neural plate folds and bulges to give rise to two optic vesicles, each of which will become an eye. The development of one eye from one of the optic vesicles is depicted here. (a) The neuroepithelium of the optic vesicle merges with the invaginating surface ectoderm, leading to induction of the lens placode. (b) The optic vesicle invaginates and the inner layer becomes the bilayered optic cup. The lens placode begins to form the lens vesicle. (c) The optic cup gives rise to the neural retina and the outer layer gives rise to the retinal pigmented epithelium (RPE). The mature eye structure with photoreceptors, interneurons, and ganglion cells is depicted. From Ali and Sowden; copyright license obtained.|
Click here to view
The early embryonic retina is a single sheet of pseudostratified neuroepithelial cells and its single class of progenitor cells gives rise to all of the retinal neurons and Müller glial cells. In contrast, the mature neural retina is comprised of six major classes of neuronal cell [Figure 3], each of which has stereotyped organization and connectivity.
|Figure 3. Chronological order of retinal cell genesis. Retinal neurogenesis (multiplication and differentiation) begins before embryonic day 10 and persists until postnatal day 11 in the mouse. Retinal cells differentiate largely in two overlapping waves: In the first wave, cone photoreceptors (cones), horizontal cells (H.C.), retinal ganglion cells (G.C.), and amacrine cells are produced; in the second wave, bipolar cells and Müller (glial) cells are produced. Rod photoreceptors (rods) are produced throughout these waves. Note there is considerable overlap during the production of various retinal cell types. The size of each wave represents the approximate proportion of each cell type in the mature retina. Modified from Young and Marquardt and Gruss, copyright licenses obtained.|
Click here to view
The cells of the mature neural retina arise in a temporal sequence which is ordered in two overlapping waves, largely conserved among vertebrates [Figure 3]. The first wave generates ganglion cells, amacrine cells and horizontal cells, along with cone photoreceptor cells. The second wave produces rod photoreceptor cells and bipolar cells, along with Müller glial cells., Although this sequence of events is largely conserved among vertebrates, the precise timing of neurogenesis and its component waves varies from species to species; in mice, the first wave begins at approximately embryonic day 11 and the second wave is complete by postnatal day 10.
The orderly exit from mitosis and subsequent differentiation in the retina is crucial for the production of properly layered retina. The regulation of cell cycle length and the mode of cytokinesis both determine whether any given cell division is symmetric or asymmetric and thereby contributes to the regulation of cell neurogenesis.
Symmetric divisions generate two daughters of the same fate: Both remain progenitors, or both become neurons. In contrast, asymmetric divisions produce daughters taking on different fates: One remains a progenitor and the other takes a neuronal fate., The plane of cytokinesis is critical in determining if the division is symmetric or asymmetric: Those cell divisions whose plane of cytokinesis is perpendicular to the surface are symmetric, whereas those being parallel to the neuroepithelial surface are asymmetric.
During early retinal development, the typical cell division is symmetric, resulting in two identical progenitor cells and leading to an increase in the pool of proliferating cells. The duration and number of these symmetric divisions is critical for regulating retinal size and sustaining genesis of later cell types. As development proceeds, the number of asymmetric divisions increases, leading to the generation of one progenitor cell and one neuron. Finally, during late retinal development, a fundamental change takes place: At this stage, symmetric divisions result in the generation of two neurons of the same type, whereas asymmetric divisions lead to the genesis of two neurons of different types.
Tight control between the number of retinal progenitor cells (RPCs) remaining proliferative and those exiting the cell cycle to take on a neuronal fate is critical in assuring a steady supply of progenitors for subsequent divisions and for regulating the size of any given pool of neurons. During the early phase of neurogenesis (during the embryonic period in mice), excessive divisions which result in neurons will deplete the pool of progenitors at the expense of late born cell types, whereas a paucity of divisions that result in neurons will increase the progenitor pool present for later-generated neurons, thereby shifting the proportion of neurons in the mature retina to normally later born types. Among the factors controlling these processes there are components of basement membranes.
| Basement Membranes: An Overview|| |
Basement membranes are cell surface associated extracellular matrices (ECMs) containing a fundamental basic "tool kit" which includes laminins, type IV collagens, nidogens and members of the heparan sulfate proteoglycan family (perlecan and agrin). Beyond providing support to cells, basement membranes establish and maintain cell polarity and associated tissues required for proper development, maturation and function of tissues.
The central scaffold of the basement membrane [Figure 4] is composed of independently assembled polymers of laminins and type IV collagen that are cross-coupled to form a network for cell attachment.,, Nidogen (also known as entactin) acts as a connecting link between two polymers of laminins and type IV collagen., The first step of assembly of basement membranes is the stabilization of laminins by sulfated glycolipids at the cell surface, leading to the nucleation of the polymerization of laminins, followed by further stabilization of laminin polymers by their binding to transmembrane receptors. Recruitment and binding of other secreted proteoglycans to the growing basement membrane results in increased stability and complexity of the basement membrane.,
|Figure 4. Laminin assembly in basement membranes. Laminins self-polymerize in the extracellular space through their LN domains and create a "nascent" scaffold. A self-assembled collagen polymer joins this scaffold, which is further linked by nidogen (Nd), perlecan (Perl) and agrin (not shown), resulting in increased stability and complexity of the basement membrane (grey surface). Laminins in the basement membrane (e.g., here, Lm-111) interact via their G domain with cell receptors including integrins (here, integrin β1 subunit shown) and dystroglycan (DG) for anchorage. Col IV, Type IV Collagen; Nd, nidogen; Perl, perlecan; Modified from Li et al, noncommercial reuse permitted by Rockefeller University Press.|
Click here to view
Basement membranes are heterogeneous, not only among different tissues, but also within a given tissue and during development. The spatial and temporal regulation of deposition of basement membrane components results from complex developmental mechanisms. Diversification in the architecture of basement membrane in different tissues and during development is due in part to variations in the composition of the basic tool kit. For example, in humans, there are 16 different isoforms of laminin and six different isoforms of collagen type IV, in addition to complex modifications of glycoproteins such as heparan sulfate and chondroitin sulfate proteoglycans. Additionally, even greater heterogeneity is brought about by growth factors that are differentially sequestered in basement membranes.,,,
Animal models with deletion or mutations in the genes encoding basement membrane molecules provide strong evidence supporting the role of basement membrane-mediated regulation in myriad cellular processes including adhesion, survival, proliferation, differentiation and migration., Basement membranes regulate essential processes in cellular behavior, in part, due to their ability to sequester growth factors and connect to the cell via cell surface receptors that modulate intracellular pathways. One family of basement membrane molecules consistently shown to be involved in providing cues for cell proliferation, polarity and survival is the laminins.
| Roles of Laminins and Their Receptors in the CNS|| |
The ectodermal lineage of the retina (and the entire CNS) implies that the basement membrane organization provides crucial guidance during retinal development. Ectodermal formation and epithelial development is critically dependent on the laminin-rich basement membrane, which confers polarity cues, regulates proliferation and provides a substrate for migration.
The central nervous system (CNS) including the brain, spinal cord and retina arises from an invagination of the primitive ectoderm, ultimately forming from a tube composed of pseudostratified neuroepithelial cells. In primates, the cranial end of this tube is massively expanded into the neocortex, a complex structure that is divided into over 50 cytoarchitectonic regions. Although the processes of CNS development have been the subjects of study for well over a hundred years, only recently have the molecular mechanisms underlying these processes become coherent.
Despite the broad array of behavior among species, the fundamentals of CNS development and connectivity are shared across many species. In general, the process of CNS development proceeds through several stereotyped phases: (1) Proliferation i.e., neurogenesis and gliogenesis during which cell populations expand from progenitors to the full complement of cells in the adult CNS and after which cells, in general, become post-mitotic; (2) neuronal migration and maturation, after terminal mitosis, during which neurons migrate from the site of genesis to their adult position and begin to take on their adult characteristics and shape; (3) neuronal axon outgrowth and target selection, through which neurons send processes varying in length from microns to meters to reach out and contact another neurons; (4) neuronal synaptogenesis, during which neurons make functional connections with each other.
All four of these developmental processes are regulated, to varying degrees, by laminins. A dramatic example is that for laminins in the cortex. Laminins are expressed in the ventricular zone of the developing neocortex,, and defects in laminins or their downstream signaling partners lead to lamination defects in the neocortex.,,
In order to understand the role of laminins in developmental processes in the CNS, simplified model systems are advantageous. Historically, one portion of the CNS, the vertebrate retina, has proven to be an excellent and very approachable model for general CNS development. The retina is easily removable; it has a relatively small number of cell types and a characteristic architecture which is generally preserved across most vertebrates. Comparable with the rest of the CNS, retinal development is a highly coordinated process that is tightly regulated by both intrinsic (genetic, cell autonomous) as well as extrinsic (epigenetic, cell non-autonomous) factors. Thus, retinal development encapsulates development of the CNS, but in a simpler manner than in other regions of the nervous system including the cortex. In order to assess the roles of laminins in development, it is necessary to analyze their expression and function.
| Laminins: Diverse Expression and Function|| |
Laminins are large heterotrimeric glycoproteins that contain an alpha chain, a beta chain and a gamma chain joined together in a coiled-coiled structure [Figure 5]. The α, b and γ chains are found in five, three and three genetic variants, respectively. Although most trimeric combinations are possible, the γ2 chain and β3 chains have been isolated only in association with each other and with the α3 chain, thereby restricting the feasible combination of the in vivo laminin heterotrimers to twenty-one of these possible trimers. Sixteen trimers have been identified in vivo, and are differentially expressed both temporally and spatially in various tissues.,,,,
|Figure 5. Simplified illustration of a laminin heterotrimer. Schematic of a prototypical laminin heterotrimer. Each chain is comprised of six domains (I-VI). The α-helical coiled-coil regions in domains I and II of the "long arm" regions of all three chains are covalently linked to one another by disulfide bonds., The self-assembly domain of each chain is responsible for self-polymerization required for basement membrane assembly. The terminal globular domain of the α chain interacts with cell surface receptors, and is responsible for communication between cells and the basement membrane. The sites for interaction of laminins with other basement membrane molecules such as nidogens (in domain III of the γ1 chain) and agrin (in the laminin "long arm" consisting of α, β and γ chains) are shown.|
Click here to view
The highly regulated developmental expression of laminins leads to distinctive biological defects upon disruption or deletion of different laminin chains. Generally, deletion of those laminin subunits which are expressed early during embryogenesis leads to lethality, whereas deletions of laminin chains expressed later in development leads to tissue-specific defects.
For example, the laminin g1 subunit is the most ubiquitously expressed laminin chain, found in most of the known heterotrimers and expressed both embryonically and extra-embryonically., Consequently, targeted deletion of the laminin g1 chain in mice results in embryonic lethality due to an arrest in blastocyst differentiation., On the other hand, deletion or mutation of the laminin α2 chain, which is expressed in skeletal and cardiac muscle, peripheral nerve, capillaries, placenta and the brain, results in postnatal lethal muscular dystrophy and peripheral nerve defects in mice and humans. Additionally, CNS defects are present in humans with mutations in the α2 chain.,, Similarly, genetic disruptions of the laminin α5 chain lead only to disruptions in the muscle, kidney and various epithelial glands.,, These data indicate that laminins may share many functional properties, however, the contribution of individual chains is specific and frequently non-redundant.
| Laminin Receptors: Linking the Extracellular Matrix to the Cell|| |
The interaction of receptors for ECM molecules with the ECM is crucial for the maintenance of cellular phenotype and tissue integrity. Perturbations of the interaction between receptors for ECM and the ECM in mice and humans lead to pathologies such as muscular dystrophies, brain and ocular dystrophies, and blistering diseases of the skin such as epidermolysis bullosa.,,,
The major receptors for laminins can be broadly classified as integrins and non-integrins. Integrins [Figure 6] are a large family of αβ heterodimers that combine to form 24 different αβ heterodimeric receptors, each with their own ligand. The αβ heterodimer which is engaged by the cell to interact with the matrix depends both on the composition of the ECM and the cell type itself. For instance, integrin α7β1 binds to laminins-211 and 221 (via the laminin α2 chain); integrins α3β1, α6β1 and α6β4 bind to laminin-332 (via the laminin α3 chain) and integrin α6β4 binds to laminins-511, 521 (via the laminin α5 chain)., Furthermore, the specific integrin αβ heterodimers bridging the ECM and the cell are also tasked with specification of the downstream signaling effectors.
|Figure 6. Integrins influence multiple functions by anchoring cells to the extracellular matrix (ECM). Integrins and dystroglycan in the extracellular space act as a bridge between the laminin-containing ECM and the cytoskeleton of the cell in the cytosol including dystrophin, resulting in changes in cell polarity, shape and migration. Integrins, after binding to the ECM, also act as signaling platforms by recruiting adaptors and signaling enzymes that control differentiation, shape and migration.|
Click here to view
The second class of laminin receptors, non-integrin receptors such as dystroglycan, plays a critical function in muscle, the central and peripheral nervous systems, the blood-brain barrier and kidney.,, Dystroglycan forms a part of the dystrophin-glycoprotein complex which interacts with other cytoskeleton molecules [Figure 6].
After translation, the dystroglycan gene product is cleaved, resulting in the production of α-dystroglycan (a peripheral membrane protein at the external surface of the membrane) and β-dystroglycan (a transmembrane protein) [Figure 6]. α-dystroglycan interacts with the ECM via high affinity interactions with the laminin α1 and α2 LG 4-5 domains. β-dystroglycan interacts with the cytoskeleton via molecules including dystrophin [Figure 6]. Although these interactions have been most extensively studied in skeletal muscle, the dystroglycan-laminin interaction is of high significance for maintenance of adhesion in multiple tissues.
There are additional non-integrin laminin receptors. These include collagen XVII (formerly known as BP180 or BPAG2), a transmembrane protein and a critical component of hemi-desmosomes associated with keratinocyte adhesion. Collagen XVII is also expressed in the CNS and the retina, where it may be important in synapse formation. A fragment of another collagen, collagen XXV, is associated with amyloid plaques in Alzheimer's disease. Other receptors associated with laminins include four types of cell-surface syndecans , and the Lutheran blood group glycoprotein, BCAM (a transmembrane protein found on erythrocyte, muscle and epithelial cells), which in addition to other functions, acts as a receptor for the α5 subunit of laminin.,
The multidomain structure of laminins, as well as the presence of different isoforms of laminin in each tissue, leads to variability in the affinity of expressed laminins towards different receptors, thereby contributing to the diverse array of laminin-mediated regulation which affects cellular functions [Figure 6]. Two retinal cell types regulated by laminins are retinal ganglion cells and Müller glial cells.
| Retinal Ganglion Cells: The Output Neurons of the Retina|| |
As the final common pathway from the retina to the brain, retinal ganglion cells (RGCs) are critical conduits for normal vision. Two aspects of RGC organization are of particular importance:First is the spatial distribution of RGCs over the surface of the retina; second is the lamination pattern of RGC dendrites in the inner plexiform layer. Various RGC subtypes exist, each with precise non-random distributions over the surface of the retina and unique connectivity in the brain. This arrangement assures that the entire visual world is sampled by diverse yet overlapping subclasses of RGC.
The physiological output of RGCs is produced upon synapsing with a particular array of retinal interneurons. This is accomplished by the production of a stereotyped pattern of dendritic development and synaptic refinement in the IPL. For example, different types of RGCs have defined patterns of dendritic arborization in the IPL in three dimensions. The first is relative to the branching from the cell body; the second is relative to the surface topography of the retina (dendritic area) and the third is relative to the depth of the IPL (dendritic lamination). Together, these spatial properties of the dendritic arbors of RGCs define the physiologic properties of the RGC that contribute to visual processing.
Thus, a thorough understanding of retinal development requires understanding how RGCs are generated; how RGC numbers are regulated; and the mechanisms of RGC dendritic development. Both intrinsic and extrinsic factors regulate this process. The number of RGCs is governed by intrinsic factors including transcriptional factors,, as well as extrinsic factors including molecules that regulate cell death  and neurotrophic molecules. In addition, adhesion  and ECM molecules , contribute to the development of GCs by acting as survival factors and promoting dendritic development.
| Müller Cells: The Principal Glial Cells of the Retina|| |
Two glial cells are present in the retina: Müller cells (MCs) and astrocytes. MCs are intrinsic to the retina and share a common progenitor with neural cells of the retina, whereas astrocytes are extrinsic to the retina and migrate into the retina via the optic nerve. During their final differentiation, retinal progenitor cells express specialized glial genes and take on glial homeostatic functions. This has led to the hypothesis that, MCs are late progenitor cells. Indeed, in non-mammalian retina MCs can be induced to regenerate neurons of the retina under experimental conditions.
MCs span the entire thickness of the neural retina and contact and ensheathe all neuronal cell bodies and processes [Figure 7]. Their structure not only provides stability to the retina, but their morphological proximity to neurons also promotes neuronal survival. In addition, this proximity to neurons may contribute to retinal information processing.,,,
|Figure 7. Müller cells are closely associated with, and interact with, all retinal neurons. The interactions among Müller cells and retinal neurons are vital to retinal homeostasis. Müller cells span nearly the entire thickness of the retina, from ILM at NFL to OLM at the junction of the inner and outer segments of PR. Neuronal somata and processes are ensheathed by the processes of Müller cells (one Müller cell is shaded pink at right). Chor, choroid; BrM, Bruch's membrane; RPE, retinal pigmented epithelium; PR, photoreceptor outer segments; OLM, outer limiting membrane; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; NFL, nerve fiber layer; ILM, inner limiting membrane; BV, blood vessel; r, R, rod photoreceptor cell; c, cone photoreceptor cell; H, horizontal cell; bc, B, bipolar cell; ac, A, amacrine cell; rgc, G, retinal ganglion cell; M, Müller cell; as, astrocyte. Left: Modified from Bringmann et al. Subject to creative commons attribution license. Right: Modified from Reichenbach et al; Reichenbach et al copyright license obtained.|
Click here to view
MCs are capable of performing multiple functions in part due to their highly polarized morphology. Among their homeostatic functions, MCs contribute to extracellular ion homeostasis  and neurotransmitter recycling. In addition, MCs promote neuronal survival by the release of neurotrophic substances. In addition, at their basal end-foot MCs make contact with the ILM using a variety of cell-matrix receptors  and at their apical surface, MCs make adhesion complexes with each other and photoreceptors forming a band of tight junctions at the outer limiting membrane. Despite its name, the outer limiting membrane is not a membrane, but rather contains components of both adherens and tight junctions.
In retinal injuries and diseases such as retinal detachment, MCs undergo reactive gliosis and manifest changes in morphology, cytoskeletal structure and the subcellular compartmentalization of ion or water channels., Reactive gliosis is characterized by alterations in biochemical and physiological functions, in addition to hypertrophy and proliferation of MCs. These changes are similar to those seen in proliferative vitreoretinopathy  and transient ischemia.
| Attachment to Retinal Basement Membranes Is Important for Retinal Architecture and Homeostasis|| |
The retina is delimited by two basement membranes: Bruch's membrane at the sclerad (outer, distal) side, and the inner limiting membrane (ILM) at the vitread (inner, proximal) side. These two membranes act as boundaries for the neural retina.
Bruch's membrane is a five-layered extracellular matrix structure located at the interface of the metabolically active retinal pigmented epithelium (RPE) and the source of nutrition for the RPE, the choriocapillaris. Bruch's membrane not only provides physical support for the RPE, it also regulates RPE differentiation and acts as a barrier that prevents choroidal neovascularization, a process in which choroidal vascular cells inappropriately invade the retina., Alterations in the composition or organization of Bruch's membrane severely compromises the normal function of RPE cells, and this disruption results in retinal pathologies including age-related macular degeneration, pseudoxanthoma elasticum and Sorsby's fundus dystrophy.
The inner limiting membrane (ILM) lies on the vitread side of the retina which is the opposite side of the retina from Bruch's membrane [Figure 7]. The ILM is not only the structural interface between the retina and the vitreous, it also provides support for the neural retina, and is responsible for organizing and maintaining the laminated structure of the retina and guiding astrocyte migration during vascular development. Disruptions or changes in the ILM are associated with retinal dysplasia as well as retinal pathologies such as diabetic retinopathy, proliferative vitreoretinopathy and retinopathy of prematurity.,
In the developing retina, RPCs adhere to the ILM via interactions between RPC basal end-feet and the ILM. Laminins are important constituents of the ILM that are likely involved in this adhesion: Major laminin subunit constituents of the ILM are α1, α5, β2, and γ1, whereas minor laminin subunit constituents of the ILM are α3, β1, γ2, and γ3.
In addition to adhesion, laminins and laminin-mediated signaling contribute to dendrite-axonal specification and neuronal development in vitro and in vivo,,, suggesting that laminins play an important role in retinal development and organization. During retinal development, RPCs undergo tightly regulated proliferation and differentiation; these processes are regulated by, inter alia, symmetrical versus asymmetrical division. Further, organization of the complex retinal structure depends on both appropriate positioning and spacing of the cells in the retina, and proper dendritic-axonal development required for the generation of functional circuitry in the retina. All of these developmental processes are influenced by laminins.
Loss of laminin-mediated signaling in the retina results in retinal dysplasia and may lead to visual impairment.,, Upon the loss of laminins, these pathologies result from disturbing the apical-basal polarity of MCs as well as the subcellular compartmentalization in MC., In addition to the contribution of laminins to MC polarity, we hypothesize that β2 and γ3 laminin chains establish apical-basal polarity in RPCs much as they do in MCs.
Adhesion to the ILM is likely important for establishing apical-basal polarity in the RPCs and required for maintaining correct timing between proliferation and neurogenesis. The ILM is also critical for MCs, the terminal progeny of RPCs, for subcellular compartmentalization of transporters, ion channels, and perhaps signaling cascade mechanisms. Finally, laminins likely provide cues to regulate RGC spacing, dendritic arborization and axonal guidance.
| Summary|| |
Adhesion to the ILM is critical in establishing the apical-basal polarity of RPCs (required for maintaining the correct timing between proliferation and neurogenesis in the retina), proper differentiation of MCs (required for compartmentalization of signaling domains to different regions of the cell) and providing cues that regulate RGC development (spacing, dendritic arborization and axonal guidance). Continued elucidation of these interactions will further advance our knowledge of retinal development and the organization of the retina's complex laminar architecture. Furthermore, this knowledge will likely have applications for regenerative studies on retinal tissue.
Financial Support and Sponsorship
NIH-NEI EY12676-13; Unrestricted Grant from Research To Prevent Blindness, Inc.
Conflicts of Interest
There are no conflicts of interest.
| References|| |
Rodieck RW. The First Steps in Seeing. Sunderland, MA: Sinauer Associates; 1998.
Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, et al.
Müller cells in the healthy and diseased retina. Prog Retin Eye Res
Dowling JE. The Retina: An Approachable Part of the Brain. Cambridge, MA: Harvard University Press; 1987.
Kolb H, Nelson R, Ahnelt P, Cuenca N. Cellular organization of the vertebrate retina. Prog Brain Res
Hynes RO. The evolution of metazoan extracellular matrix. J Cell Biol
Bryant DM, Mostov KE. From cells to organs: Building polarized tissue. Nat Rev Mol Cell Biol
Arimura N, Kaibuchi K. Neuronal polarity: From extracellular signals to intracellular mechanisms. Nat Rev Neurosci
Tahirovic S, Bradke F. Neuronal polarity. Cold Spring Harb Perspect Biol
Krummel MF, Macara I. Maintenance and modulation of T cell polarity. Nat Immunol
Etienne-Manneville S. Polarity proteins in glial cell functions. Curr Opin Neurobiol
Paulsson M. Basement membrane proteins: Structure, assembly, and cellular interactions. Crit Rev Biochem Mol Biol
Yurchenco PD. Basement membranes: Cell scaffoldings and signaling platforms. Cold Spring Harb Perspect Biol
2011;3. pii: A004911.
Nelson CM, Bissell MJ. Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Ann Rev Cell Dev Bio
Akhtar N, Streuli CH. An integrin-ILK-microtubule network orients cell polarity and lumen formation in glandular epithelium. Nat Cell Biol
Ljubimov AV, Burgeson RE, Butkowski RJ, Couchman JR, Zardi L, Ninomiya Y, et al.
Basement membrane abnormalities in human eyes with diabetic retinopathy. J Histochem Cytochem
Yurchenco PD, Cheng YS, Campbell K, Li S. Loss of basement membrane, receptor and cytoskeletal lattices in a laminin-deficient muscular dystrophy. J Cell Sci
Ruiz-Torres MP, López-Ongil S, Griera M, Díez-Marqués ML, Rodríguez-Puyol M, Rodríguez-Puyol D. The accumulation of extracellular matrix in the kidney: Consequences on cellular function. J Nephrol
Kuo DS, Labelle-Dumais C, Gould DB. COL4A1 and COL4A2 mutations and disease: Insights into pathogenic mechanisms and potential therapeutic targets. Hum Mol Genet
Kim SH, Chu YK, Kwon OW, McCune SA, Davidorf FH. Morphologic studies of the retina in a new diabetic model; SHR/N:Mcc-cp rat. Yonsei Med J
Tang J, Mohr S, Du YD, Kern TS. Non-uniform distribution of lesions and biochemical abnormalities within the retina of diabetic humans. Curr Eye Res
Agathocleous M, Harris WA. From progenitors to differentiated cells in the vertebrate retina. Annu Rev Cell Dev Biol
Turner DL, Cepko CL. A common progenitor for neurons and glia persists in rat retina late in development. Nature
Malicki J. Cell fate decisions and patterning in the vertebrate retina: The importance of timing, asymmetry, polarity and waves. Curr Opin Neurobiol
Rapaport DH, Wong LL, Wood ED, Yasumura D, LaVail MM. Timing and topography of cell genesis in the rat retina. J Comp Neurol
Randlett O, Norden C, Harris WA. The vertebrate retina: A model for neuronal polarization in vivo
. Dev Neurobiol
Kechad A, Jolicoeur C, Tufford A, Mattar P, Chow RW, Harris WA, et al.
Numb is required for the production of terminal asymmetric cell divisions in the developing mouse retina. J Neurosci
Ohnuma S, Harris WA. Neurogenesis and the cell cycle. Neuron
Young RW. Cell differentiation in the retina of the mouse. Anat Rec
Yurchenco PD, Patton BL. Developmental and pathogenic mechanisms of basement membrane assembly. Curr Pharm Des
Durbeej M. Laminins. Cell Tissue Res
Timpl R. Macromolecular organization of basement membranes. Curr Opin Cell Biol
Li S, Harrison D, Carbonetto S, Fassler R, Smyth N, Edgar D, et al.
Matrix assembly, regulation, and survival functions of laminin and its receptors in embryonic stem cell differentiation. J Cell Biol
Li S, Liquari P, McKee KK, Harrison D, Patel R, Lee S, et al.
Laminin-sulfatide binding initiates basement membrane assembly and enables receptor signaling in Schwann cells and fibroblasts. J Cell Biol
Iozzo RV, Cohen IR, Grässel S, Murdoch AD. The biology of perlecan: The multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem J
Miner JH, Yurchenco PD. Laminin functions in tissue morphogenesis. Annu Rev Cell Dev Biol
Van Agtmael T, Bruckner-Tuderman L. Basement membranes and human disease. Cell Tissue Res
Wiradjaja F, DiTommaso T, Smyth I. Basement membranes in development and disease. Birth Defects Res C Embryo Today
Campos LS, Leone DP, Relvas JB, Brakebusch C, Fässler R, Suter U, et al.
Beta1 integrins activate a MAPK signalling pathway in neural stem cells that contributes to their maintenance. Development
Lathia JD, Patton B, Eckley DM, Magnus T, Mughal MR, Sasaki T, et al.
Patterns of laminins and integrins in the embryonic ventricular zone of the CNS. J Comp Neurol
Radakovits R, Barros CS, Belvindrah R, Patton B, Müller U. Regulation of radial glial survival by signals from the meninges. J Neurosci
Marchetti G, Escuin S, van der Flier A, De Arcangelis A, Hynes RO, Georges-Labouesse E. Integrin alpha5beta1 is necessary for regulation of radial migration of cortical neurons during mouse brain development. Eur J Neurosci
Barak T, Kwan KY, Louvi A, Demirbilek V, Saygi S, Tüysüz B, et al.
Recessive LAMC3 mutations cause malformations of occipital cortical development. Nat Genet
Cheng YS, Champliaud MF, Burgeson RE, Marinkovich MP, Yurchenco PD. Self-assembly of laminin isoforms. J Biol Chem
Patton BL. Laminins of the neuromuscular system. Microsc Res Tech
Aumailley M, Bruckner-Tuderman L, Carter WG, Deutzmann R, Edgar D, Ekblom P, et al.
A simplified laminin nomenclature. Matrix Biol
Kabosova A, Azar DT, Bannikov GA, Campbell KP, Durbeej M, Ghohestani RF, et al.
Compositional differences between infant and adult human corneal basement membranes. Invest Ophthalmol Vis Sci
Smyth N, Vatansever HS, Murray P, Meyer M, Frie C, Paulsson M, et al.
Absence of basement membranes after targeting the LAMC1 gene results in embryonic lethality due to failure of endoderm differentiation. J Cell Biol
Li S, Edgar D, Fässler R, Wadsworth W, Yurchenco PD. The role of laminin in embryonic cell polarization and tissue organization. Dev Cell
Miyagoe Y, Hanaoka K, Nonaka I, Hayasaka M, Nabeshima Y, Arahata K, et al.
Laminin alpha2 chain-null mutant mice by targeted disruption of the Lama2 gene: A new model of merosin (laminin 2)-deficient congenital muscular dystrophy. FEBS Lett
Colognato H, Yurchenco PD. Form and function: The laminin family of heterotrimers. Dev Dyn
Miner JH, Cunningham J, Sanes JR. Roles for laminin in embryogenesis: Exencephaly, syndactyly, and placentopathy in mice lacking the laminin alpha5 chain. J Cell Biol
Miner JH, Li C. Defective glomerulogenesis in the absence of laminin alpha5 demonstrates a developmental role for the kidney glomerular basement membrane. Dev Biol
Rebustini IT, Patel VN, Stewart JS, Layvey A, Georges-Labouesse E, Miner JH, et al.
Laminin alpha5 is necessary for submandibular gland epithelial morphogenesis and influences FGFR expression through beta1 integrin signaling. Dev Bio
Salih MA, Sunada Y, Al-Nasser M, Ozo CO, Al-Turaiki MH, Akbar M, et al.
Muscular dystrophy associated with beta-Dystroglycan deficiency. Ann Neurol
Kim JN, Namgung R, Kim SC, Lee MG, Lee JS, Lee C. Pyloric atresia with junctional epidermolysis bullosa (PA-JEB) syndrome: Absence of detectable beta4 integrin and reduced expression of epidermal linear IgA dermatosis antigen. Int J Dermatol
Culligan K, Glover L, Dowling P, Ohlendieck K. Brain dystrophin-glycoprotein complex: Persistent expression of beta-dystroglycan, impaired oligomerization of Dp71 and up-regulation of utrophins in animal models of muscular dystrophy. BMC Cell Biol
Moore SA, Saito F, Chen J, Michele DE, Henry MD, Messing A, et al.
Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature
Delcommenne M, Streuli CH. Control of integrin expression by extracellular matrix. J Biol Chem
Streuli CH, Akhtar N. Signal co-operation between integrins and other receptor systems. Biochem J
Tian M, Jacobson C, Gee SH, Campbell KP, Carbonetto S, Jucker M. Dystroglycan in the cerebellum is a laminin alpha 2-chain binding protein at the glial-vascular interface and is expressed in Purkinje cells. Eur J Neurosci
Masaki T, Matsumura K. Biological role of dystroglycan in Schwann cell function and its implications in peripheral nervous system diseases. J Biomed Biotechnol
Kojima K, Nosaka H, Kishimoto Y, Nishiyama Y, Fukuda S, Shimada M, et al.
Defective glycosylation of a-dystroglycan contributes to podocyte flattening. Kidney Int
Franzke CW, Tasanen K, Schäcke H, Zhou Z, Tryggvason K, Mauch C, et al.
Transmembrane collagen XVII, an epithelial adhesion protein, is shed from the cell surface by ADAMs. EMBO J
Claudepierre T, Manglapus MK, Marengi N, Radner S, Champliaud MF, Tasanen K, et al.
Collagen XVII and BPAG1 expression in the retina: Evidence for an anchoring complex in the central nervous system. J Comp Neurol
Hashimoto T, Wakabayashi T, Watanabe A, Kowa H, Hosoda R, Nakamura A, et al.
CLAC: A novel Alzheimer amyloid plaque component derived from a transmembrane precursor, CLAC-P/collagen type XXV. EMBO J
Ogawa T, Tsubota Y, Hashimoto J, Kariya Y, Miyazaki K. The short arm of laminin gamma2 chain of laminin-5 (laminin-332) binds syndecan-1 and regulates cellular adhesion and migration by suppressing phosphorylation of integrin beta4 chain. Mol Biol Cell
Bachy S, Letourneur F, Rousselle P. Syndecan-1 interaction with the LG4/5 domain in laminin-332 is essential for keratinocyte migration. J Cell Physiol
Udani M, Zen Q, Cottman M, Leonard N, Jefferson S, Daymont C, et al.
Basal cell adhesion molecule/lutheran protein. The receptor critical for sickle cell adhesion to laminin. J Clin Invest
Parsons SF, Lee G, Spring FA, Willig TN, Peters LL, Gimm JA, et al.
Lutheran blood group glycoprotein and its newly characterized mouse homologue specifically bind alpha5 chain-containing human laminin with high affinity. Blood
Gan L, Xiang M, Zhou L, Wagner DS, Klein WH, Nathans J. POU domain factor Brn-3b is required for the development of a large set of retinal ganglion cells. Proc Natl Acad Sci U S A
Yao J, Sun X, Wang Y, Xu G, Qian J. Math5 promotes retinal ganglion cell expression patterns in retinal progenitor cells. Mol Vis
Harder JM, Ding Q, Fernandes KA, Cherry JD, Gan L, Libby RT. BCL2L1 (BCL-X) promotes survival of adult and developing retinal ganglion cells. Mol Cell Neurosci
Marler KJ, Poopalasundaram S, Broom ER, Wentzel C, Drescher U. Pro-neurotrophins secreted from retinal ganglion cell axons are necessary for ephrinA-p75NTR-mediated axon guidance. Neural Dev
Fuerst PG, Bruce F, Rounds RP, Erskine L, Burgess RW. Cell autonomy of DSCAM function in retinal development. Dev Biol
Deiner MS, Kennedy TE, Fazeli A, Serafini T, Tessier-Lavigne M, Sretavan DW. Netrin-1 and DCC mediate axon guidance locally at the optic disc: Loss of function leads to optic nerve hypoplasia. Neuron
Ogata-Iwao M, Inatani M, Iwao K, Takihara Y, Nakaishi-Fukuchi Y, Irie F, et al.
Heparan sulfate regulates intraretinal axon pathfinding by retinal ganglion cells. Invest Ophthalmol Vis Sci
Roesch K, Jadhav AP, Trimarchi JM, Stadler MB, Roska B, Sun BB, et al.
The transcriptome of retinal Müller glial cells. J Comp Neurol
Goldman D. Müller glial cell reprogramming and retina regeneration. Nat Rev Neurosci
Reichenbach A, Stolzenburg JU, Eberhardt W, Chao TI, Dettmer D, Hertz L. What do retinal müller (glial) cells do for their neuronal 'small siblings'? J Chem Neuroanat
Reichenbach A, Ziegert M, Schnitzer J, Pritz-Hohmeier S, Schaaf P, Schober W, et al.
Development of the rabbit retina. V. The question of 'columnar units'. Brain Res Dev Brain Res
Newman E, Reichenbach A. The Müller cell: A functional element of the retina. Trends Neurosci
Reichenbach A, Faude F, Enzmann V, Bringmann A, Pannicke T, Francke M, et al.
The Müller (glial) cell in normal and diseased retina: A case for single-cell electrophysiology. Ophthalmic Res
Nagelhus EA, Horio Y, Inanobe A, Fujita A, Haug FM, Nielsen S, et al.
Immunogold evidence suggests that coupling of K siphoning and water transport in rat retinal Müller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia
Bringmann A, Iandiev I, Pannicke T, Wurm A, Hollborn M, Wiedemann P, et al.
Cellular signaling and factors involved in Müller cell gliosis: Neuroprotective and detrimental effects. Prog Retin Eye Res
Claudepierre T, Dalloz C, Mornet D, Matsumura K, Sahel J, Rendon A. Characterization of the intermolecular associations of the dystrophin-associated glycoprotein complex in retinal Müller glial cells. J Cell Sci
Williams DS, Arikawa K, Paallysaho T. Cytoskeletal components of the adherens junctions between the photoreceptors and the supportive Müller cells. J Comp Neurol
Omri S, Omri B, Savoldelli M, Jonet L, Thillaye-Goldenberg B, Thuret G, et al.
The outer limiting membrane (OLM) revisited: Clinical implications. Clin Ophthalmol
Fisher SK, Lewis GP, Linberg KA, Verardo MR. Cellular remodeling in mammalian retina: Results from studies of experimental retinal detachment. Prog Retin Eye Res
Sethi CS, Lewis GP, Fisher SK, Leitner WP, Mann DL, Luthert PJ, et al.
Glial remodeling and neural plasticity in human retinal detachment with proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci
Francke M, Weick M, Pannicke T, Uckermann O, Grosche J, Goczalik I, et al.
Upregulation of extracellular ATP-induced Müller cell responses in a dispase model of proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci
Hirrlinger PG, Pannicke T, Winkler U, Claudepierre T, Varshney S, Schulze C, et al.
Genetic deletion of laminin isoforms ß2 and ?3 induces a reduction in Kir4.1 and aquaporin-4 expression and function in the retina. PLoS One
Del Priore LV, Geng L, Tezel TH, Kaplan HJ. Extracellular matrix ligands promote RPE attachment to inner Bruch's membrane. Curr Eye Res
Gong J, Sagiv O, Cai H, Tsang SH, Del Priore LV. Effects of extracellular matrix and neighboring cells on induction of human embryonic stem cells into retinal or retinal pigment epithelial progenitors. Exp Eye Res
Booij JC, Baas DC, Beisekeeva J, Gorgels TG, Bergen AA. The dynamic nature of Bruch's membrane. Prog Retin Eye Res
Gnanaguru G, Bachay G, Biswas S, Pinzón-Duarte G, Hunter DD, Brunken WJ. Laminins containing the ß2 and ?3 chains regulate astrocyte migration and angiogenesis in the retina. Development
Balasubramani M, Schreiber EM, Candiello J, Balasubramani GK, Kurtz J, Halfter W. Molecular interactions in the retinal basement membrane system: A proteomic approach. Matrix Biol
Dénes V, Witkovsky P, Koch M, Hunter DD, Pinzón-Duarte G, Brunken WJ. Laminin deficits induce alterations in the development of dopaminergic neurons in the mouse retina. Vis Neurosci
Randlett O, Poggi L, Zolessi FR, Harris WA. The oriented emergence of axons from retinal ganglion cells is directed by laminin contact in vivo
Wright KM, Lyon KA, Leung H, Leahy DJ, Ma L, Ginty DD. Dystroglycan organizes axon guidance cue localization and axonal pathfinding. Neuron
Satz JS, Philp AR, Nguyen H, Kusano H, Lee J, Turk R, et al.
Visual impairment in the absence of dystroglycan. J Neurosci
Edwards MM, Mammadova-Bach E, Alpy F, Klein A, Hicks WL, Roux M, et al.
Mutations in Lama1 disrupt retinal vascular development and inner limiting membrane formation. J Biol Chem
Pinzón-Duarte G, Daly G, Li YN, Koch M, Brunken WJ. Defective formation of the inner limiting membrane in laminin beta2-and gamma3-null mice produces retinal dysplasia. Invest Ophthalmol Vis Sci
Schultze M. Anatomy and Physiology of the Retina. Bonn: Verlag von Max Cohen & Son; 1866.
Ramon Y Cajal S. The Structure of the Retina 1892; in translation, Thorpe SA, Glickstein M, Translators. Springfield (IL): Thomas; 1972.
Ali RR, Sowden JC. Regenerative medicine: DIY eye. Nature
Marquardt T, Gruss P. Generating neuronal diversity in the retina: One for nearly all. Trends Neurosci
Cooper AR, Kurkinen M, Taylor A, Hogan BL. Studies on the biosynthesis of laminin by murine parietal endoderm cells. Eur J Biochem
Antonsson P, Kammerer RA, Schulthess T, Hänisch G, Engel J. Stabilization of the alpha-helical coiled-coil domain in laminin by C-terminal disulfide bonds. J Mol Biol
Mayer U, Kohfeldt E, Timpl R. Structural and genetic analysis of laminin-nidogen interaction. Ann N Y Acad Sci
Denzer AJ, Schulthess T, Fauser C, Schumacher B, Kammerer RA, Engel J, et al.
Electron microscopic structure of agrin and mapping of its binding site in laminin-1. EMBO J
Bringmann A, Grosche A, Pannicke T, Reichenbach A. GABA and glutamate uptake and metabolism in retinal glial (Müller) cells. Front Endocrinol (Lausanne)
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
|This article has been cited by|
||Early posterior vitreous detachment is associated with LAMA5 dominant mutation
| ||Filomena Napolitano,Valentina Di Iorio,Giuseppe Di Iorio,Mariarosa Anna Beatrice Melone,Fernando Gianfrancesco,Francesca Simonelli,Teresa Esposito,Francesco Testa,Simone Sampaolo |
| ||Ophthalmic Genetics. 2018; : 1 |
|[Pubmed] | [DOI]|
||Identification of the first dominant mutation of LAMA5 gene causing a complex multisystem syndrome due to dysfunction of the extracellular matrix
| ||Simone Sampaolo,Filomena Napolitano,Alfonsina Tirozzi,Mafalda Giovanna Reccia,Luca Lombardi,Olimpia Farina,Adriano Barra,Ferdinando Cirillo,Mariarosa Anna Beatrice Melone,Fernando Gianfrancesco,Giuseppe Di Iorio,Teresa Esposito |
| ||Journal of Medical Genetics. 2017; 54(10): 710 |
|[Pubmed] | [DOI]|
||Epithelial disruptions, but not immune cell invasion, induced secretory dysfunction following innate immune activation in a novel model of acute salivary gland injury
| ||Abeer Shaalan,Guy Carpenter,Gordon Proctor |
| ||Journal of Oral Pathology & Medicine. 2017; |
|[Pubmed] | [DOI]|
||Architecture in 3D cell culture: An essential feature for in vitro toxicology
| ||Sophie A. Lelièvre,Tim Kwok,Shirisha Chittiboyina |
| ||Toxicology in Vitro. 2017; |
|[Pubmed] | [DOI]|
||Retinal Proteoglycans Act as Cellular Receptors for Basement Membrane Assembly to Control Astrocyte Migration and Angiogenesis
| ||Chenqi Tao,Xin Zhang |
| ||Cell Reports. 2016; 17(7): 1832 |
|[Pubmed] | [DOI]|