Table Of ContentThe Retinal
Müller Cell
PERSPECTIVESINVISIONRESEARCH
Series Editor: Colin Blakemore
University of Oxford
Oxford, England
Biochemistry of the Eye
ElaineR.Berman
Development of the Vertebrate Retina
Edited by Barbara L. Finlay and Dale R. Sengelaub
ParallelProcessingintheVisualSystem
THECLASSIFICATIONOFRETINALGANGLIONCELLSANDITSIMPACTON
THENEUROBIOLOGYOFVISION
Jonathan Stone
Presbyopia Research
FROM MOLECULAR BIOLOGY TO VISUAL ADAPTATION
Editedby Gérard Obrechtand LawrenceW. Stark
The Retinal Müller Cell
STRUCTUREANDFUNCTION
Vijay Sarthy and Harris Ripps
Visual Development
Nigel W. Daw
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The Retinal
Müller Cell
Structure and Function
Vijay Sarthy
Northwestern University Medical School
Chicago,Illinois
and
Harris Ripps
UniversityofIllinoisCollegeofMedicine
Chicago,Illinois
Kluwer Academic Publishers
New York, Boston, Dordrecht, London, Moscow
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Print ISBN: 0-306-46470-5
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To Mary andJeanne
Preface
The human brain contains more than a billion neurons which interconnect
to form networks that process, store, and recall sensory information. These
neuronal activities are supported by a group of accessory brain cells collec-
tively known as neuroglia. Surprisingly, glial cells are ten times more nu-
merous than neurons, and occupy more than half the brain volume (Hydén,
1961). Although long considered a passive, albeit necessary, component of
the nervous system, many interesting and unusual functional properties of
glial cells are only now being brought to light. As a result, the status of these
cellular elements is approaching parity with nerve cells as a subject for
experimental study.
The term glia (or glue) seems today to be a misnomer in view of the
diverse functions attributed to glial cells. Experimental studies in the last
three decades have clearly established that the behavior of glial cells is far
from passive, and thatthey are atleastas complex as neuronswith regard to
their membrane properties. In addition, glial cells are of importance in
signal processing, cellular metabolism, nervous system development, and
the pathophysiology of neurological diseases. The Müller cell of the verte-
brate retina provides a splendid example of an accessory cell that exhibits
features illustrating every aspect of the complex behavior now associated
with glial cells.
HISTORICAL PERSPECTIVE
It was more than a century ago that the generic term neuroglia was given
to the non-neuronal elements of the nervous system. The notion that neural
elements are embedded in an unusual connective tissue-like matrix (Binde-
gewebe) can be traced to the early writings of the eminent German patholo-
gist Rudolph Virchow (1846), but the concept of neuroglia (Nervenkitt)
and a description of its histological form did not appear until ten years later
(Virchow, 1856; for a historical review, see Somjen, 1988). Without detract-
ing from Virchow’s enormous prescience, it is worth noting that five years
earlier Heinrich Müller (1851), having studied a variety of species, provided
vii
viii PREFACE
a detailed description of the radial fibers which we now know to be the
principal glial cell of the vertebrate retina. (The text of Müller’s landmark
paper, together with a translation, is provided in the Appendix.) Shortly
thereafter, Kolliker (1854) observed similar structures in the human retina
and ascribed to them eponymously the name by which they have come to be
known: the Müller cells.
It is also interesting to note that whereas glial cells of the central ner-
vous system (CNS) have been classified into a number of subtypes based on
such distinguishing features as morphology, antigenicity, and functional
properties (Raff, 1989), Müller cells are usually treated as belonging to a
unique but functionally uniform class of glial cell. This is clearly not the
case. Depending upon the species, there is a striking heterogeneity in
Müller cell structure, antigenic properties, and responses to neurotransmit-
ters. However, the molecular determinants of these differences are often
unknown, and no rational basis for subclassification of Müller cells has
emerged. The observed differences between species may reflect the differ-
ent metabolic or functional demands on these cells, or the influence of
different environmental factors; a comparative study of Müller cells from
this perspective is sorely needed.
In focusing on the Müller cell, we cannot ignore the wealth of informa-
tion available from the study of glial cells in other regions of the CNS.
Indeed, many of the defining characteristics of Müller cells, such as their
electrical properties, immunochemical features, metabolic activities, and
cytoplasmic content, display similarities to those found in protoplasmic
astrocytes (Kettenman and Ransom, 1995). Nevertheless, the Müller cell has
become highly adapted in form and function to its retinal environment, and
there is little to be gained by attempting to force it into one or another of the
conventional categories of neuroglia.
SCOPE OF THE BOOK
Chapter 1 introduces the glial cells of the retina and describes their
structural features and intercellular relationships. The morphology of Müller
cells is considered in detail, with special attention paid to junctional con-
tacts, membrane characteristics, and other cytological features. Chapter 2
deals with the role of Müller cells in retinal development and also with
features of Müller cell development itself. The lineage, birth, and deter-
mination of Müller cells are reviewed. Potential roles of Müller cells in
neuronal development are also discussed. Chapter 3 looks at the metabolic
interactions between Müller cells and retinal neurons. The involvement of
Müller cells in energy metabolism, transmitter inactivation, pH regulation,
PREFACE ix
and retinoid metabolism are discussed. Chapter 4 focuses on the signaling
pathways between retinal neurons and Müller cells. The properties of neu-
rotransmitter transporters and receptors on Müller cells are described.
Chapter 5 discusses ionic properties of the Müller cell membranes, the role
of Müller cells in potassium homeostasis, and the involvement of Müller
cells in generating electroretinographic (ERG) potentials. Last, Chapter 6
presents an overview of the involvement of Müller cells in retinal pathology.
This chapter describes putative roles of Müller cells in excitotoxicity, reac-
tive gliosis, and retinal diseases.
It will be clear from the information presented in these chapters that
Müller cells perform a variety of tasks in the retina. Perhaps their best
understood functions are in potassium homeostasis and in neurotransmit-
ter uptake and metabolism. These activities support a number of vital
processes in the normal retina. Müller cells play an active role in patholog-
ical conditions as well. For instance, in ischemic retina, Müller cells are
likely to alleviate glutamate excitotoxicity by removing excess extracellular
glutamate. The strong gliotic response of Müller cells also suggests a role in
the phagocytosis of cell debris and scar formation. Moreover, it has recently
been discovered that reactive Müller cells produce neuroprotective cyto-
kines and neurotrophic factors that alleviate neuronal damage and degen-
eration. In contrast, our current knowledge of the mechanisms that deter-
mine Müller cell fate and the roles of Müller cells in retinal development is
still in its infancy.
In writing this book, we have attempted to survey the current status of
our knowledge of Müller cell structure and function with the hope that this
effort will point out areas of Müller cell biology that need to be addressed in
the future. Because of space constraints, we have been selective in our
choice of topics and illustrations. Many similar or related examples have not
been presented, and we apologize if we overlooked any important studies.
Clearly, the content and emphasis of the book reflects our personal view of
Müller cell biology. Although many details are still lacking, it is evident now
that Müller cells and retinal neurons have evolved together to fashion an
intricate cellular network, the retina, whose ultimate goal is to present a
clear view of the surrounding world.
ACKNOWLEDGMENTS
We gratefully acknowledge the generosity of our colleagues who pro-
vided illustrations and data from their published work, and the publishers
who very graciously permitted us to reproduce figures. We are especially
thankful to Paul Witkovsky, Jack Saari, Tom Reh, Don Puro, Lee Jampol,
x PREFACE
Steve Fisher, and Ruben Adler for helpful comments and suggestions on
individual chapters. This book could not have been completed without
the enthusiastic assistance of Jane Zakevicius, Mary Winneke of the UIC
library, and the library staffs of the Marine Biological Laboratory, Woods
Hole, Massachusetts, and Friday Harbor Laboratory, Friday Harbor, Wash-
ington. We are grateful to Lisa Birmingham who meticulously prepared all
the illustrations, and we thank Tom Porter, Michael Schütte, Etha Schuette,
and Rolf Behrmann for undertaking the challenging task of translating
Müller’s original report.
Contents
1. Structural Organization of Retinal Glia ...................... 1
1.1. Müller Cells ......................................... 1
1.1.1. Relation toNeurons ............................ 5
1.1.2. IntercellularJunctions........................... 9
1.1.3. Müller CellsasInsulators........................ 13
1.1.4. The Zonula Adherens of the Outer Limiting
Membrane..................................... 14
1.1.5. TheConfines of the SubretinalSpace ............. 17
1.1.6. TheBlood–RetinaBarrier ....................... 18
1.1.7. TheInternal LimitingMembrane ................. 22
1.1.8. Cytoskeleton ................................... 24
1.1.9. OrthogonalArrays .............................. 26
1.2.Astrocytes andMicroglia .............................. 28
1.2.1. Astrocytes...................................... 28
1.2.2. Microglia ...................................... 33
2. Role inRetinal Development .............................. 35
2.1. Lineage,Birthdate,andDevelopment of Müller Cells ..... 36
2.1.1. Lineage Relationship between Müller Cells and
RetinalNeurons ................................ 36
2.1.2. Lineage Relationship with Astrocytes and Microglia 38
2.1.3. TheBirth of Müller Cells ........................ 39
2.1.4. MüllerCellDetermination ....................... 42
2.2. Roles inRetinalDevelopment .......................... 47
2.2.1. Neuronal Migration and Retinal Histogenesis ...... 48
2.2.2. ExtrinsicMolecules inRetinal Development ....... 51
2.2.3. CellAdhesionReceptors ......................... 52
2.2.4. ExtracellularMatrixMolecules andIntegrins ....... 56
................
2.2.5. Growth andNeurotrophicFactors 57
2.2.6. RetinoicAcid .................................. 60
2.3. Developmental Regulationof GeneExpression ......... .. 61
xi
