Phil. Trans. R. Soc.

B (2011) 366, 1190–1192

doi:10.1098/rstb.2010.0377

Introduction

The ocular lens: a classic model for

development, physiology and disease
I. Michael Wormstone1 and Michael A. Wride2,*
1
School of Biological Sciences, University of East Anglia, Norwich, East Anglia NR4 7TJ, UK
2
Ocular Development and Neurobiology Research Group, Zoology Department, School of Natural Sciences,
Trinity College Dublin, Dublin 2, Republic of Ireland
Millions are rendered blind or exhibit visual impairment due to pathologies of the lens of the eye.
Lens research therefore addresses the direct need to gain insights into the cellular and molecular
basis of disease, but, moreover, serves as a valuable experimental system to answer fundamental bio-
logical questions. This themed issue showcases the scientific knowledge of the processes involved in
the development, structure, ultrastructure, physiology and pathology of the lens and how this infor-
mation has the potential to significantly further knowledge in various fields of research. The issue is
divided into three main areas. Firstly, the lens is discussed as a developmental model for embryonic
induction, as an elegant system for studying the role of growth factors in development, and for
analysis of the molecular control and cellular basis of cellular differentiation. The genetic basis of
disorders of lens development, including paediatric cataract (lens opacity), are also discussed in
this section. Secondly, adult lens structure and ultrastructure are covered, as well as the lens as a
model for homeostasis and solute exchange. Finally, the papers in the latter part of the special
issue review lens pathology, including the lens as a model for normal and pathological ageing,
vitreoretinal influences on lens function and cataract and the lens as a model for fibrotic disease.
Overall, the articles highlight the lens as a continuing, very important and attractive model
system for biologists working in many different research areas.
Keywords: lens; physiology; disease

1. INTRODUCTION the lens, together with the expression and ordered

The lens is a uniquely transparent structure with many packing of crystallin proteins, permits lens transparency
interesting properties, which has been referred to as the to be maintained for significant periods of life.
‘sparkling jewel’ of anatomy [1]. The lens is derived Multiple factors can lead to cataract, which is defined
from the surface ectoderm. Following the formation of as any opacity of the lens resulting in significant vari-
the lens vesicle, cells lying on the posterior surface ations in the refractive index of the lens over distances
elongate towards the epithelial cells covering the similar to the wavelength of transmitted light. According
anterior surface to form the primary fibre cell popu- to the latest estimates, 18 million people are blind from
lation. The adult lens is isolated from other tissues, cataract as identified by the World Health Organisation
has neither neural innervation nor a vascular system (WHO) (http://www.who.int/blindness/causes/priority/
and therefore receives all required nutrients from the en/index1.html). Cataract is defined by its age of onset
aqueous and vitreous humours with which it is and can be classified as congenital, juvenile, pre-senile
bathed. As cell death in the normal lens is restricted, or senile (age-related) with different proportions of gen-
overall growth is fundamentally regulated by cell etic and environmental influences on the aetiology of
division rates. Proliferation occurs exclusively at the these various classifications. Furthermore, there are a
equatorial region in the adult lens from a putative number of different types of cataract, which have differ-
stem cell population [2], while cells of the central ent phenotypes and occur via different cellular and
anterior epithelium are quiescent. In addition, the molecular mechanisms. Thus, in order to understand
lens equator is the site at which fibre cell differentia- the reasons for cataract, it is necessary to investigate
tion begins, involving massive cellular elongation and the cellular and molecular basis of lens development
degradation of all intracellular organelles, including and physiology.
the nucleus. The discrete organization of cells within Indeed, the lens has long been used as a tractable
model system in which to investigate fundamentally
important biological processes and principles. There-
* Author for correspondence ([email protected]). fore, this themed issue comprises articles about wide
One contribution of 10 to a Theme Issue ‘The ocular lens: a classic ranging aspects of lens biology that are of relevance
model for development, physiology and disease’. to many other fields.
1190 This journal is q 2011 The Royal Society
 Introduction. Lens development, physiology and disease I. M. Wormstone & M. A. Wride 1191

The lens has been used as a classical developmental and redundant signalling and proteolytic pathways are
model system for many years. Hans Spemann was emerging as players in lens fibre cell differentiation and
awarded the Nobel Prize for Physiology or Medicine that these pathways often form interacting networks.
in 1936 for his work on the organizer-effect in embryo- Therefore, it is argued in this article that the various sig-
nic development and embryonic induction (http:// nalling pathways employed during lens fibre cell
nobelprize.org/nobel_prizes/medicine/laureates/1935/ differentiation and organelle loss may functionally com-
spemann-lecture.html). Many of Spemann’s key pensate for each other in response to mutations in or
observations and insights about embryonic and tissue- knockouts of certain genes involved in this process.
specific inductive processes were obtained from This is highly important given the importance of lens
investigating the induction of the lens in the ectoderm clarity for correct vision.
during very early embryonic development resulting Indeed, the lens is pivotal for the development of
in formation of a lens placode. Currently, striking the eye and mutations in genes important in lens
advances are being made in the field of lens induction, development can have serious consequences for
particularly its molecular basis (e.g. the role of specific vision. Amanda Churchill and Jochen Graw highlight
growth factors and tissue interactions in developmental clinical and experimental advances in congenital and
determination and patterning events) and these are paediatric cataracts in their article [6]. These authors
providing fundamentally important insights into induc- cover the genetic analysis of families with vision
tive processes in development in general. The article defects, including discussion of various mutations in
here by Lena Gunhaga addresses these issues, specifi- genes coding for transcription factors, for example
cally focusing on how individual signalling molecules, FoxE3, Maf and Pitx3, structural proteins such as
including bone morphogenetic proteins (BMPs), fibro- crystallins and connexins, metabolic pathways includ-
blast growth factors (FGFs), Wnts and Shh, regulate ing enzymes involved in sugar metabolism, such as
the initial specification of lens placodal cells and the galactose, and, intriguingly, axon guidance molecules.
progressive development of the lens via the coordination Furthermore, mouse cataract mutants are reviewed
of both molecular and tissue interactions [3]. and the point is made that, since many of the genes
The lens has also been an important model system mutated in lens defects are also expressed outside the
for studying the mechanisms that govern cellular eye, cataracts may act as early and readily detectable
differentiation following exposure to growth factors, biomarkers for a number of systemic syndromes.
and in the article by Lovicu and colleagues these As revealed by advances in laser scanning confocal
issues are addressed, focusing on the lens as a wonder- microscopy and electron microscopy, the lens has a
ful tool to dissect out these processes in time and space unique structure and ultrastructure, which can appear
using various animal models [4]. The use of transgenic deceptively simple, but is essential for its efficient
and gene knockout techniques in the lens is a rapidly function. Indeed, the lens has been something of a test
advancing area of research that provides important organ for techniques in laser scanning confocal
new insights into the role of growth factors and their microscopy. Steve Bassnett and colleagues discuss the
receptors in developmental patterning events and this structure and ultrastructure of the lens and make the
area is discussed in this article. In particular, the recent point that various structural adaptations serve to mini-
development of crystallin-cre mice is allowing lens- mize light scatter, enabling the lens to function as
epithelial and fibre-cell-specific deletion of selected ‘biological glass’ [7]. The lens must remain transparent
genes in particular compartments of the lens when to maintain its function and therefore provides valuable
these mice are crossed with mice possessing floxed information relating to tissue construction and design.
genes. Several of these studies, using the lens as a tract- An important aspect in maintaining lens transparency
able model system, have provided important insights is regulation of solutes. Ralf Dahm and colleagues
into the roles of Wnt, BMP and FGF signalling address this issue and draw light upon the mechanisms
in proliferation, migration and differentiation during controlling transport and exchange in the vertebrate
embryonic development in general, which are also lens, which include: paracellular transport, membrane
discussed in this article. transport by specific carriers and transporters, gap junc-
Degradation processes occurring during lens fibre tional transport and transcellular transport by coated
cell differentiation are essential for lens clarity. Michael vesicles [8].
Wride addresses this area in which rapid advances are The ability of the lens to remain transparent for
currently being made in parallel with improved under- so long is a considerable biological achievement. How-
standing of the intracellular signalling and proteolytic ever, when the exquisite order of the lens is disrupted,
pathways involved [5]. In this context, the lens is being or cannot be maintained effectively, cataract results.
used to investigate aspects of cell survival and the emer- Age is the major risk factor associated with cataract
ging insights being obtained into the use of apoptosis and the relationship between ageing and age-related
signalling pathways for differentiation rather than cell cataract is addressed by Ralph Michael and Tony
death per se, although controversies and doubts remain Bron [9]. In this article, three forms of cataract that
about the relative roles of effector and initiator caspases have different aetiology are discussed. Nuclear cataract
in this process, for example. Further work reveals affects the central fibre cells (the lens nucleus) and is
that other proteolytic enzymes such as cathepsins and associated with post-translational modification of pro-
calpains as well as the ubiquitin proteasome (UPP) teins in this region. This results in accumulation of
system are also important in this process, and the inter- fluorescent chromophores and greater potential oxida-
actions and importance of these pathways is reviewed. tion, which, in turn, causes cross-linking of proteins
Furthermore, the point is made that multiple, parallel and light scatter. In many ways, nuclear cataract is
Phil. Trans. R. Soc. B (2011)
1192 I. M. Wormstone & M. A. Wride Introduction. Lens development, physiology and disease

believed to be an acceleration of the natural ageing also highlight that clinical solutions to cataract are
process. Cortical cataract affects the peripheral dependent on gaining insights into the basic cellular
lens fibre cells and is associated with changes in mem- and molecular mechanisms employed during lens devel-
brane permeability and ion imbalance. For example, opment and homeostasis.
cortical cataracts exhibit very high intracellular cal- We therefore hope that this themed issue will act as
cium concentrations. Age-related mechanisms that an inspiration to new generations of scientists to
can influence the onset of cortical cataract are also become engaged by the unique and fascinating proper-
discussed. Posterior subcapsular cataract results from ties of the lens. We are passionate that such further
an inability of lens epithelial cells to form new fibre engagement with the lens will facilitate scientists in
cells. Subsequently, these cells grow across the pos- answering important questions in their own particular
terior capsule and form subcapsular plaques, thereby fields of biological/clinical interest.
giving rise to light scatter. The cellular basis for this
condition is fascinating and provides valuable infor-
mation relating to biological cues within an organ, We would like to wholeheartedly thank all of the authors for
and is therefore highlighted. It is also evident that agreeing to contribute to this issue and for providing an
excellent set of articles that will no doubt stand the test of
modification to the local environment can influence
time. We would also like to extend our deep appreciation
lens cell function. to all the reviewers of the articles, who freely gave of their
David Beebe and colleagues address this issue in time and energy and who always provided timely, excellent
relation to the vitreous humour [10]. The oxygen and constructive comments on the manuscripts.
levels at the posterior surface of the lens are low, but
it is argued that breakdown of the vitreous will increase
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Phil. Trans. R. Soc. B (2011)