Extracellular matrix and integrin signaling in lens development and cataract

doi:10.1016/j.semcdb.2006.10.006

Seminars in Cell & Developmental Biology

Volume 17, Issue 6, December 2006, Pages 759-776

https://doi.org/10.1016/j.semcdb.2006.10.006 Get rights and content

Abstract

During development of the vertebrate lens there are dynamic interactions between the extracellular matrix (ECM) of the lens capsule and lens cells. Disruption of the ECM causes perturbation of lens development and cataract. Similarly, changes in cell signaling can result in abnormal ECM and cataract. Integrins are key mediators of ECM signals and recent studies have documented distinct repertoires of integrin expression during lens development, and in anterior subcapsular cataract (ASC) and posterior caspsule opacification (PCO). Increasingly, studies are being directed to investigating the signaling pathways that integrins modulate and have identified Src, focal adhesion kinase (FAK) and integrin-linked kinase (ILK) as downstream kinases that mediate proliferation, differentiation and morphological changes in the lens during development and cataract formation.

Introduction

The lens constitutes an important model for investigating and understanding molecular and cellular mechanisms that underlie inductive interactions during development. These mechanisms have been shown to be relevant for understanding pathogenesis of cataract. Much progress has been made in elucidating many of the growth factor signaling pathways and transcription factors involved in these processes. However, the interactions between lens cells and their unique extracellular matrix (ECM), the lens capsule, have been less well studied. Interrogation of NCBI/PubMed reveals there are more than 33,000 published papers on integrins, but fewer than 60 of these relate to lens. The doubling of published papers in this area in the last 5 years reflects the increasing interest that is being focused on the role of the ECM and matrix receptors in lens biology.

This review provides a brief overview of the function and structure of the integrin family of extracellular matrix receptors and reviews the progress that has been made in understanding the involvement of extracellular matrix and integrins in lens development and pathology. The large amount of data that has accumulated on integrin biology, particularly over the last 10 years, precludes a comprehensive review of integrin structure and function, and we have referred readers in many instances to other specialist reviews. It is hoped that this review will stimulate further research into these important molecules and help focus efforts on the many unanswered questions about their role in lens biology and pathology.

Section snippets

Lens development and growth

Initiation of lens formation during embryogenesis is the result of a series of inductive interactions [1], [2]. Ocular morphogenesis commences when bilateral evaginations of the embryonic forebrain, the optic vesicles come into contact with overlying head ectoderm. At this region of intimate contact, the ectoderm thickens to form the lens placode and the neuroepithelium forms the retinal disc. Coordinated invagination of these structures forms the lens pit and optic cup, respectively. The optic

Cell–ECM interactions in the lens: the lens capsule

Both epithelial and fiber cells are intimately associated with a thick basement membrane, which encapsulates the lens and separates cells from the ocular media. Thus, signaling molecules from the ocular media must traverse the lens capsule matrix before stimulating receptors on the cell surface. As the lens differentiates, there are concomitant changes in the capsule matrix, suggesting that it plays dynamic roles in lens development. Similarly, in ASC, there are significant alterations in the

Integrins–mediators of ECM signals

Integrins are a large family of glycosylated, heterodimeric, transmembrane, cell adhesion molecules that mediate principally cell–ECM interactions but are also implicated in cell–cell interactions. Each heterodimer consists of one α and one β subunit that associate non-covalently through their extracellular domains to produce a functional receptor. To date, 18 α and 8 β mammalian subunits have been described and are known to form 24 distinct receptors (Table 1) that each bind to a specific

Integrin gene knockouts

The essential role of integrins is reflected by the number of subunit null mutants that show lethality at peri-implantation (β1), embryonic (α4, α5, αv, β8) or perinatal (α3, α6, α8, α9, β4) stages of development. By contrast, null mutants of several subunits (α1, α2, α7, α10, αIIb, αL, αM, αE, β2, β3, β5, β6, β7) are viable and fertile and show less severe phenotypes [66], [78], [79], [80]. Three mutants result in phenotypes that model human diseases (α7, muscular dystrophy; β3, Glanzman

Integrins in lens development

The lens has been shown to express several integrin subunits at various stages of development. Expression surveys noted expression of α2 [81] and α6A [74] subunits in embryonic mouse lens, as well as many other tissues. Studies of embryonic chick lens showed the presence of α3 and α6 but not α1, α5 or αv subunits [82]. However, more recent studies suggest that these and other subunits are expressed at varying levels and stages of development.

Low levels of α1 subunit have been detected in the

Integrins and abnormal lens development

The expression of various integrin subunits has been documented in clinical cataract specimens [85], [111], [112], [113], [114]. However, in most cases the types of cataract were poorly defined and as cataracts can arise in different parts of the lens and from many different causes [115], [116], it is difficult to make meaningful conclusions from, or comparisons among, these studies. A general observation is that cataractous lenses express subunits (α2, α3, α6, β1) that are present in the

‘Inside-out’ integrin signaling

Integrins can exist in active or inactive conformations [137], [138], [139]. Regulation of the affinity state of integrins occurs via ‘inside-out’ signaling, which involves conformational changes in integrin structure that allow the extracellular globular head domain to engage and bind ligands. A currently favoured model [66] is that inactive integrins are in a bent conformation that makes the globular head less accessible to ligand (Fig. 1). This bent state of the integrin dimer results from

‘Outside-in’ integrin signaling

Integrins have been shown to influence numerous intracellular signaling pathways, leading to cell survival, cell cycle regulation, cell differentiation and migration via actin cytoskeleton regulation and adhesion complex remodelling. However, as integrins do not have intrinsic kinase activity, other kinases need to be recruited to propagate these signals (Fig. 1). Once integrins are activated and bind extracellular ligands, the cytoplasmic tails can bind various cytoplasmic proteins, which in

Focal adhesion kinase (FAK)

FAK is non-receptor tyrosine kinase, identified on the basis of its phosphorylation by v-Src, and is a major focal adhesion-associated protein. It is activated by a range of stimuli including integrin clustering, growth factor, and G-protein-linked receptor activation and it links integrins to the cytoskeleton and intracellular signaling [150], [151], [152], [153]. FAK comprises N- and C-terminal domains, flanking an internal catalytic region. The N-terminal domain interacts with receptor

FAK in the lens

FAK is expressed from early stages of lens morphogenesis and in the mature lens becomes restricted to regions where cells exit the cell cycle (posterior germinative zone) and initiate differentiation (transitional zone) ([156], unpublished data). FAK is also present in the basal membrane complex of lens fiber cells, which remains attached to the lens capsule when this is separated from the fiber mass [93], and it is suggested that it functions not only as an adhesion complex protein but also as

Integrin-linked kinase (ILK)

ILK is a serine-threonine kinase that binds the cytoplasmic tails of β1, β2, and β3 subunits. It is widely expressed and localizes to cell-matrix adhesions. Its N-terminal domain has four ankyrin repeats that mediate binding to several cytoplasmic proteins such as ILKAP and particularly interesting Cys-His-rich protein (PINCH). It is via PINCH binding to the adaptor protein Nck2 that ILK is linked to growth factor tyrosine kinase receptors (Fig. 1). The C-terminal domain is a serine-threonine

ILK in the lens

We have recently shown that ILK is weakly expressed in normal postnatal lens but is up-regulated in TGFβ transgenic lenses [12] (Fig. 4C and D). Transfection of LEC with ILK expressing constructs induces a morphological change that resembles EMT, whereas transfection with a kinase-dead form of ILK inhibited the morphological transformation of LEC by TGFβ. However, in neither case was there evidence of changes in molecular markers of EMT (fibronectin, α-smooth muscle actin), suggesting the

Conclusions

In the last 5 years, increased attention has focused on the role of integrins and the ECM in lens biology. Significant progress has been made in identifying the repertoires of integrins expressed during development and in ASC and PCO. During development there is expression of a cohort of integrins that matches the ligands present in the lens capsule. Moreover, as LEC differentiate into fibers there are changes in integrin expression mediated by differentiation factors in the vitreous, including

Acknowledgements

This work was supported by grants from the NHMRC (Australia) and Sydney Foundation for Medical Research to RDI. Support was provided by the Australian Research Council as an Australian Postgraduate Award to EDW. The authors gratefully acknowledge Prof. Arnoud Sonnenberg (Netherlands Cancer Institute, Amsterdam) and Prof. Elizabeth Georges-Labouesse (Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg) for providing access to ocular material from their integrin mutant

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¹: Present address: Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada V5Z1L3.

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ReviewExtracellular matrix and integrin signaling in lens development and cataract

Abstract

Introduction

Section snippets

Lens development and growth

Cell–ECM interactions in the lens: the lens capsule

Integrins–mediators of ECM signals

Integrin gene knockouts

Integrins in lens development

Integrins and abnormal lens development

‘Inside-out’ integrin signaling

‘Outside-in’ integrin signaling

Focal adhesion kinase (FAK)

FAK in the lens

Integrin-linked kinase (ILK)

ILK in the lens

Conclusions

Acknowledgements

Dev Biol

Exp Eye Res

Tissue Cell

Differentiation

Matrix Biol

Prog Retin Eye Res

J AAPOS

Dev Biol

Matrix Biol

Cell Biol Int

Exp Eye Res

Genomics

J Biol Chem

Lab Invest

Differentiation

Differentiation

Exp Eye Res

Exp Eye Res

Exp Eye Res

Exp Eye Res

J Biol Chem

Cell

J Biol Chem

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Trends Genet

Matrix Biol

Exp Cell Res

Am J Pathol

Exp Eye Res

Exp Eye Res

J Cataract Refract Surg

Dev Biol

Early eye development in vertebrates

Annu Rev Cell Dev Biol

Lens induction and determination

Lens development

Eye

Minireview: apoptosis as seen through a lens

Apoptosis

Proteases in eye development and disease

Birth Defects Res C Embryo Today

Nuclear cataract caused by a lack of DNA degradation in the mouse eye lens

Nature

WNT/Frizzled signaling in eye development and disease

Front Biosci

Wnt signaling enhances FGF2-triggered lens fiber cell differentiation

Development

Requirement for TGFbeta receptor signaling during terminal lens fiber differentiation

Development

Transforming growth factor-beta-induced epithelial-mesenchymal transition in the lens: a model for cataract formation

Cells Tissues Organs

Colocalization of laminin and fibronectin in bovine lens epithelial cells in vitro

In Vitro Cell Dev Biol

The roles of laminin and fibronectin in the development of the lens capsule

Curr Eye Res

Binding of FGF-1 and FGF-2 to heparan sulphate proteoglycans of the mammalian lens capsule

Growth Factors

Tenascin Mr 220,000 isoform expression correlates with corneal cell migration

Development

Immunohistochemical and molecular genetic evidence for type IV collagen alpha5 chain abnormality in the anterior lenticonus associated with Alport syndrome

Arch Ophthalmol

Review
Extracellular matrix and integrin signaling in lens development and cataract