The Cornea through the Eyes of Knockout Mice

Chakravarti, Shukti

doi:10.1006/exer.2001.1055

Cited by 25 publications

(12 citation statements)

References 43 publications

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“…The production of mice with KSPG-null mutations has facilitated research into the respective and combined functions of these molecules in the control of extracellular matrix morphogenesis (28)(29)(30). Broadly stated, of the three KSPGs in cornea, lumican and keratocan are required to maintain collagen fibrils in a specific spatial conformation (13)(14)(15)(16)(17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

Matrix morphogenesis in cornea is mediated by the modification of keratan sulfate by GlcNAc 6- O -sulfotransferase

Hayashida

Akama

Beecher

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Matrix assembly and homeostasis in collagen-rich tissues are mediated by interactions with proteoglycans (PGs) substituted with sulfated glycosaminoglycans (GAGs). The major GAG in cornea is keratan sulfate (KS), which is N-linked to one of three PG core proteins. To ascertain the importance of the carbohydrate chain sulfation step in KS functionality, we generated a strain of mice with a targeted gene deletion in Chst5, which encodes an N-acetylglucosamine-6-O-sulfotransferase that is integral to the sulfation of KS chains. Corneas of homozygous mutants were significantly thinner than those of WT or heterozygous mice. They lacked high-sulfated KS, but contained the core protein of the major corneal KSPG, lumican. Histochemically stained KSPGs coassociated with fibrillar collagen in WT corneas, but were not identified in the Chst5-null tissue. Conversely, abnormally large chondroitin sulfate͞dermatan sulfate PG complexes were abundant throughout the Chst5-deficient cornea, indicating an alteration of controlled PG production in the mutant cornea. The corneal stroma of the Chst5-null mouse exhibited widespread structural alterations in collagen fibrillar architecture, including decreased interfibrillar spacing and a more spatially disorganized collagen array. The enzymatic sulfation of KS GAG chains is thus identified as a key requirement for PG biosynthesis and collagen matrix organization.collagen ͉ glycosaminoglycans ͉ proteoglycans G lycosaminoglycans (GAGs) substituted on proteoglycans (PGs) are influential in defining collagen fibrillar architecture in a wide range of connective tissue matrices. Keratan sulfate (KS) is an important constituent of several collagen-rich tissues and is the major GAG in cornea where it is N-linked to asparagine residues in one of three PG core proteins: lumican (1), keratocan (2), and mimecan͞osteoglycin (3). Human corneal GlcNAc 6-O-sulfotransferase (also known as human GlcNAc6ST-5 and GST4␤) is the responsible enzyme for the synthesis of high-sulfated KS via the transfer of sulfate onto the GlcNAc 6-O position of the KS backbone (4).Fairly compelling evidence exists for a regulatory role for KSPGs in the maintenance of corneal matrix structure in a number of species. The avian cornea in ovo, for example, synthesizes an unsulfated form of KS midway through development when it is structurally disorganized and transmits relatively little light, but switches to produce a sulfated KS GAG as it becomes transparent and attains a more well ordered collagen fibrillar ultrastructure (5, 6). KS sulfation patterns are also altered in opaque, structurally disorganized corneal scar tissue in rabbits (7,8) and in cloudy human corneas with the inherited disease, macular corneal dystrophy (9), which is caused by mutations in CHST6, a gene encoding human corneal GlcNAc 6-O-sulfotransferase (10).Hybrid type I͞V collagen fibrils are the cornea's main nonspecular light-scattering elements and are formed into wide, interweaving belts or lamellae that lie approximately in the tissue plane (11). Wit...

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Section: Discussionmentioning

confidence: 99%

Matrix morphogenesis in cornea is mediated by the modification of keratan sulfate by GlcNAc 6- O -sulfotransferase

Hayashida

Akama

Beecher

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…It is increasingly evident, however, that biological processes that regulate assembly or the higher order organization of the collagenous matrix are likely to contribute to these disorders. The small leucine-rich repeat proteoglycans (SLRP) have emerged as a significant multimember group, expressed at high levels in many collagenous tissues and capable of binding and regulating collagen fibril assembly and growth, likely to be important in these disorders (1,4,15,16). Along this line, Morquio syndrome or mucopolysaccharidoses IV is associated with genetic defects in enzymes involved in the degradation of keratan sulfates, glycosaminoglycan side chains of connective tissue proteoglycans (4).…”

Section: (Eds Oi) II (Stickler) Iii (Eds) V (Eds) Xi (Sticklermentioning

confidence: 99%

A Syndrome of Joint Laxity and Impaired Tendon Integrity in Lumican- and Fibromodulin-deficient Mice

Jepsen

Wu²,

Peragallo

et al. 2002

Journal of Biological Chemistry

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205

174

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Lumican and fibromodulin regulate the assembly of collagens into higher order fibrils in connective tissues. Here, we show that mice deficient in both of these proteoglycans manifest several clinical features of Ehlers-Danlos syndrome. The Lum ؊/؊ Fmod ؊/؊ mice are smaller than their wild type littermates and display gait abnormality, joint laxity, and age-dependent osteoarthritis. Misaligned knee patella, severe knee dysmorphogenesis, and extreme tendon weakness are the likely causes for joint laxity in the double-nulls. Fibromodulin deficiency alone leads to significant reduction in tendon stiffness in the Lum ؉/؉ Fmod ؊/؊ mice, with further loss in stiffness in a Lum gene dose-dependent way. At the protein level, we show marked increase of lumican in Fmod ؊/؊ tendons, which may partially rescue the tendon phenotype in this genotype. These results establish fibromodulin as a key regulator and lumican as a modulator of tendon strength. A disproportionate increase in small diameter immature collagen fibrils and a lack of progression to mature, large diameter fibrils in the Fmod ؊/؊ background may constitute the underlying cause of tendon weakness and suggest that fibromodulin aids fibril maturation. This study demonstrates that the collagen fibril-modifying proteoglycans, lumican and fibromodulin, are candidate genes and key players in the pathogenesis of certain types of Ehlers-Danlos syndrome and other connective tissue disorders.

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“…The cornea is a unique connective tissue that combines tensile strength, protection against microbial infections, transparency and refractive power for correct vision (Hay 1979;Maurice 1957;Hay and Revel 1969;Chakravarti 2001). The corneal epithelium is five to seven cell-layered, where the innermost undifferentiated basal cells continue to divide to provide daughter cells that differentiate as they move to the outer layers to replace sloughed off cells.…”

Section: Introductionmentioning

confidence: 99%

Differential gene expression patterns of the developing and adult mouse cornea compared to the lens and tendon

Lee

Schumacher

et al. 2008

Experimental Eye Research

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The cornea continues to mature after birth to develop a fully functional, refractive and protective barrier tissue. Here we investigated the complex biological events underlying this process by profiling global genome-wide gene expression patterns of the immature postnatal day 10 and seven week-old adult mouse cornea. The lens and tendon were included in the study to increase the specificity of genes identified as up regulated in the corneal samples. Notable similarities in gene expression between the cornea and the tendon were in the mesenchymal extracellular matrix collagen (types I, III, V, VI) and proteoglycan (lumican, decorin and biglycan) genes. Expression similarities in the cornea and lens were limited to certain epithelial genes and the crystallins. Approximately 76 genes were over expressed in the cornea samples that showed basal expression levels in the lens and tendon. Thirty-two of these were novel with no known functions in the cornea. These include genes with a potential role in protection against oxidative stress (Dhcr24, Cdo1, Akr1b7, Prdx6), inflammation (Ltb4dh, Wdr1), ion-transport (Pdzk1ip1, Slc12a2, Slc25a17) and transcription (Zfp36l3, Pdzk1ip1). Direct comparison of the cornea of two ages showed selective up regulation of 50 and 12 genes in the P10 and adult cornea, respectively. Of the up regulated P10 genes several encode extracellular matrix collagens and proteoglycans that are stable components of the adult cornea and their high transcriptional activity at P10 indicate a period of active corneal growth and matrix deposition in the young cornea. Much less is known about the genes selectively over expressed in the adult cornea; some relate to immune response and innervation (Npy), and possibly to electron transport (Cyp24a1, Cyp2f2) and others of yet unknown functions in the cornea (Rgs10, Psmb8, Xlr4)). This study detected expression of genes with known functions in the cornea, providing additional validation of the microarray experiments. Importantly, it identified several novel genes whose functions have not been investigated in the cornea.

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The Cornea through the Eyes of Knockout Mice

Cited by 25 publications

References 43 publications

Matrix morphogenesis in cornea is mediated by the modification of keratan sulfate by GlcNAc 6- O -sulfotransferase

Matrix morphogenesis in cornea is mediated by the modification of keratan sulfate by GlcNAc 6- O -sulfotransferase

A Syndrome of Joint Laxity and Impaired Tendon Integrity in Lumican- and Fibromodulin-deficient Mice

Differential gene expression patterns of the developing and adult mouse cornea compared to the lens and tendon

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