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Prog Mol Biol Transl Sci. Author manuscript; available in PMC 2017 October 25.
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Published in final edited form as:

Prog Mol Biol Transl Sci. 2015 ; 134: 119–127. doi:10.1016/bs.pmbts.2015.04.006.

Overview of the Lens

J. Fielding Hejtmancik* and Alan Shiels†,1
*Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of
Health, Bethesda, Maryland, USA
†Department of Ophthalmology and Visual Sciences, Washington University School of Medicine,
St. Louis, Missouri, USA
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Abstract
In order to accomplish its function of transmitting and focusing light, the crystalline lens of the
vertebrate eye has evolved a unique cellular structure and protein complement. These distinct
adaptations have provided a rich source of scientific discovery ranging from biochemistry and
genetics to optics and physics. In addition, because of these adaptations, lens cells persist for the
lifetime of an organism, providing an excellent model of the aging process. The chapters dealing
with the lens will demonstrate how the different aspects of lens biology and biochemistry combine
in this singular refractive organ to accomplish its critical role in the visual system.

1. INTRODUCTION
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Like the lens in a camera, the basic function of the eye lens is to transmit and focus light
onto the retina. To facilitate this, it contains one of the highest concentrations of proteins of
any tissue. The lens has been studied scientifically for over a century, beginning in 1833
when Sir David Brewster deduced the fine structure of the cod lens using only a candle and a
finely ruled steel bar.1 In 1894, Mörner first described high concentrations of soluble
structural proteins we now call crystallins,2 and Spemann developed the concept of inductive
interactions in development by studying the lens in 1901.3 Renwick mapped a cataract locus,
one of the first autosomal loci to be localized,4 and chicken lens δ-crystallins were among
the first mRNAs to be isolated and cloned.5 Thus, in addition to being important in the study
of inherited diseases, the lens has also been a model system invaluable for developmental
and structural biology.
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2. STRUCTURE AND CELLS OF THE LENS

Weighing about 65 mg at birth, the human lens increases in weight to about 160 mg by the
age of 10 at which time growth slows substantially so that it weighs about 250 mg by the age
of 90.6,7 As much as 60% of the total mass of the lens can be made up of proteins, much
higher than almost any other tissue.8 The lens is surrounded by a collagenous capsule, on
which the anterior-facing basal poles of the epithelial cells rest, as do the basal poles of the
fiber cells facing posteriorly (Fig. 1).9,10 The capsule acts as a barrier to diffusion and

1
Corresponding author [email protected].
 Hejtmancik and Shiels Page 2

contributes to shaping the lens during accommodation.11,12 Its main components are type IV
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collagen, laminin, entactin, perlecan, type XVIII collagen, heparin sulfate proteoglycan, and
fibronectin,13,14 of which the first four are major structural molecules that self-assemble to
form a matrix. The capsular filaments, of uniform size and aligned in a parallel fashion, are
thinnest at the posterior pole and thicken to a maximum at the equator, where the lens
zonules insert.14 Fibrillin and elastin fibers also integrate in the equatorial region, especially
in the outer zonular.15 The lens capsule is first detectable at 5–6 weeks of gestation in
humans16 and is produced continually throughout life12 anteriorly by the cuboidal
epithelium and more slowly posteriorly by the fiber cells.

Mitotic division in the lens occurs in the germinative zone of the anterior epithelium located
just anterior to the equator. The anterior epithelial cells of the lens are connected by gap
junctions,17 allowing exchange of low-molecular-weight metabolites and ions. They have
few or no tight junctions that would make the extracellular spaces impermeable to these
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molecules.18,19 Anterior cuboidal epithelial cells also are rich in organelles and contain large
amounts of cytoskeletal proteins such as microtubules, spectrin, α-actinin, actin, myosin,
and vimentin, presumably to help stabilize the cell structures during accommodation.20–22
Both lens epithelial and especially fiber cells contain large amounts of crystallins.

Fiber cells make up the lens nucleus. Layers of nucleated cortical fiber cells form highly
ordered concentric shells around the nonnucleated central fiber cells which make up the fetal
nucleus, with the ends of the peripheral fiber cells abutting in sutures anteriorly and
posteriorly. Both the ordered arrangement of the fiber cells and their sutures as well as their
intracellular structure are important for light transmission and lens transparency.23–25 Also
contributing to transparency is the presence of only minimal extracellular space between
fiber cells, which have many interdigitations.9,26 Junctional complexes between adjacent
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fiber cells allow for exchange of metabolites.21,22 Lens crystallins, which make up about
90% of the water-soluble protein, are the main soluble components of fiber cells, along with
cytoskeletal components, including actin, myosin, vimentin, α-actinin, and microtubules.27

The lens is composed of a single cell type that follows a developmental pattern, beginning as
a member of the germinative zone in the single layer of anterior epithelial cells overlaying
the fiber cell mass.26 Epithelial cells then migrate laterally toward the equator, where they
begin to elongate and invert to form secondary fibers. In order to increase light transmission,
organelles such as mitochondria, Golgi bodies, and both rough and smooth ER are degraded
in the differentiating lens fiber cells so that they are absent from nuclear fiber cells. The
density of their cell membranes increases, approaching that of the cytoplasm, which also
decreases light scattering.28 As the cells elongate newer cortical fiber cells are layered over
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them so that they are moved toward the lens nucleus, stretching anteriorly from the cuboidal
epithelial cells posteriorly to the posterior capsule. Transcriptional control plays a significant
role in the differential synthesis of lens crystallins (see Ref. 29). The distribution of β-
crystallin mRNAs in chickens30 and the β- and γ-crystallin proteins and mRNAs in rats31,32
provides examples of the spatial and temporal control of crystallin gene expression during
lens development.

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3. TRANSPARENCY
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The main optical function of the lens is to transmit light, focusing it on the retina. The
cornea contributes about 80% of total refraction, while the lens fine-tunes the focusing of
light onto the retina. Although the human lens is colorless at birth, there is a gradual increase
in yellowish pigmentation with age33 probably due to the production of 3-
hydroxykynurenine and other metabolites of tryptophan that filter UV light.34 The lens
transmits light with wavelengths up to 1200 nm efficiently, but transmits very little light
below 390 nm. 1200 nm is well above the limit of visual perception, about 720 nm. As
discussed previously, the architecture and cellular contents of the lens are critical for its
transparency. The transparency and high-refractive index of cells in the lens result from tight
packing of their proteins, providing a constant refractive index over distances approximating
the wavelength of the transmitted light.24,25 In fact, as lens proteins are diluted to
concentrations below that found in the lens, about 450 mg/ml, light scattering actually
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increases,35,36 because dilution decreases the weak interactions between unlike proteins that
occur at high concentrations and help to maintain lens transparency.37,38 Finally, there is a
gradual increase in the refractive index of the human lens from 1.38 (73–80% H2O) in the
cortex to 1.42 (68%H2O) in the nucleus, in part due to an enrichment of tightly packed γ-
crystallins.39

4. AGING
The inability of cells to be replaced in the encapsulated lens combined with the inability of
lens cell proteins to turn over in the nonnucleated fiber cells makes the lens particularly
susceptible to damage with aging and environmental insults such as UV light and other
oxidative stresses.40 This results in a decrease in transmission of light and focusing even in
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the normal aged lens so that the intensity of light reaching the retina is reduced by about 10-
fold by 80 years of age.41 It also increases susceptibility to senescent cataract and
presbyopia, especially in individuals exposed to environmental insults or having a genetic
proclivity.42 With increasing age, vacuoles and multilamellar bodies develop between lens
fiber cells, occasionally disrupting the fiber plasma membrane.43 In addition, most of the
elaborate cytoskeletal structure found in lens cells disappears with age,44 so that by the fifth
decade presbyopia develops with loss of the ability to accommodate.45,46

Enzymatic activity in the lens decreases with age, especially in the central cells of the lens
nucleus where the cells are older than those in the cortical nucleus and especially the
anterior epithelial cells.47 This compromised intracellular homeostasis might be exacerbated
by the decreased metabolic coupling of the active cortex and the inactive nucleus that occurs
in older lenses, in part associated with decreased gap junction coupling.48,49 This is
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particularly relevant for the enzymes that produce a reducing environment by maintaining
high levels of reduced glutathione, such as glutathione reductase and glucose-6-phosphate
dehydrogenase.50 Decreases in the activity of these and other reducing enzymes decrease
defenses against oxidative damage in the lens and exacerbate damage to crystallins and other
metabolic support systems.51 Finally, as the lens ages intracellular Na+ and Ca2+
concentrations rise, probably due to an increase in lens permeability or decrease in ion
channel pumping efficiency.52

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Lens crystallins also show age-related changes that might interfere with lens transparency.37
Between 10 and 50 years of age crystallin modification increases,53 as does the level of
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high-molecular-weight aggregates and water-insoluble protein.54 Because of their chaperone

activity, this is especially notable in the α-crystallins, but is also seen in the β- and γ-
crystallins.55,56 Crystallins, membranes, and enzymes are also cleaved and partially
degraded, including the nonenzymatic cleavage of αA-crystallin at the bond between
Asn101 and Glu102.57 In what might be a positive feedback effect, cleavage products of
βA3-crystallin appear to inhibit the chaperone activity of α-crystallin chaperone.58 γ-
Crystallins, and particularly γS-crystallin, are often subject to proteolysis, degradation, and
modification in age-dependent cataracts, being broken down to low-molecular-weight
peptides.59–61

As the lens ages both the amino- and carboxyl-terminal arms of up to half of the intrinsic
membrane protein AQP0 (MP26) molecules undergo proteolysis, forming MP22.62 Other
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posttranslational modifications of AQP0 also occur with aging including C-terminal

phosphorylation, possibly involved in intercellular trafficking, and glycation, which
influences AQP0 interaction with calmodulin. However, the precise functional significance
of these remains unclear.63,64 The lens contains proteasomes, which preferentially degrade
oxidized proteins65 tagged with the protease cofactor ubiquitin,66 whose activity is increased
by oxidative stress.67 These proteinases are balanced during aging by inhibitors including
the chaperones HSP90 and α-crystallin.59

Covalent modifications of crystallins and other lens proteins also increase with aging, with
increases in oxidation of methionine, deamidation of asparagine and glutamine residues,
disulfide bridges, backbone cleavage, and racemization of aspartic acid residues.59,68,69
Deamidation can destabilize βA3-crystallin, causing it to aggregate,70 while deamidation of
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glutamines at the interface of γD-crystallin can also destabilize it.71 Asp151 in αA-
crystallin is especially susceptible to racemization because it forms a succinimide
intermediate easily.72 Racemization at both Asp58 and Asp151 can lead to increased
aggregation and decreased chaperone activity and is enhanced by mutations of nearby
residues.73 Finally, phosphorylation and nonenzymatic glycosylation (glycation) also occur,
especially affecting the ε-amino groups of lysine residues.57,74,75 These can participate in
the Maillard reaction, resulting in nondisulfide covalent cross-links, increased pigmentation,
and nontryptophan fluorescence.76 Glycation of α-crystallin can also decrease its chaperone
function, eventually resulting in aggregation. 77 Lens proteins can also undergo
carbamylation with aging or other insult, and this can induce cataract,78 which has been
proposed to be the mechanism of cataract associated with chronic diarrhea and its resultant
uremia.79 Thus, the development and biology of the lens is directed at establishing
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transparency and focusing of light, and then defending this highly specialized system against
damage by age and environmental insults.

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Figure 1.
Human lens structure. Anterior epithelial cells divide at the 10 and 2 o’clock positions. Cells
then move laterally, eventually inverting in the bow region, at which time they elongate and
begin degrading their organelles to form cortical fiber cells. Central nuclear fiber cells
elongate from the posterior epithelia early in development. The ends of the more peripheral
secondary fiber cells abut at the sutures, which are shown here as vertical lines but are seen
clinically as the anterior and posterior Y structures.
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