Lumican regulates collagenous matrix assembly as a keratan sulfate proteoglycan in the cornea and is also present in the connective tissues of other organs and embryonic corneal stroma as a glycoprotein. In normal unwounded cornea, lumican is expressed by stromal keratocytes. Our data show that injured mouse corneal epithelium ectopically and transiently expresses lumican during the early phase of wound healing, suggesting a potential lumican functionality unrelated to regulation of collagen fibrillogenesis, e.g. modulation of epithelial cell adhesion or migration. An anti-lumican antibody was found to retard corneal epithelial wound healing in cultured mouse eyes. Healing of a corneal epithelial injury in Lum ؊/؊ mice was significantly delayed compared with Lum ؉/؊ mice. These observations indicate that lumican expressed in injured epithelium may modulate cell behavior such as adhesion or migration, thus contributing to corneal epithelial wound healing.Rapid re-epithelialization is essential for restoration of homeostasis in injured tissues; impaired healing of injured epithelium increases the risks of infection and further damage underlying tissues (1, 2). The cornea provides an ideal model to evaluate interactions of migrating epithelial cells and the extracellular matrix of the underlying basement membrane during wound healing because epithelial injuries of the avascular corneal tissue heal in a bloodless wound field. Various specific proteins such as vinculin (3), keratins (4), CD44 hyaluronan receptors (5), and gelatinases and metalloproteinase inhibitors (6, 7) are up-regulated during corneal epithelial wound healing. These proteins are believed to modulate cell adhesion or migration.Lumican belongs to the family of small leucine-rich proteoglycans (SLRPs) 1 that includes keratocan, mimecan, decorin, biglycan, fibromodulin, epiphycan, and osteoadherin. In the cornea, lumican, keratocan, and mimecan are modified with keratan sulfate glycosaminoglycan chains comprising the keratan sulfate proteoglycans (KSPG) of the stromal extracellular matrix (8 -13). In normal unwounded mouse cornea, lumican mRNA is expressed in stromal keratocytes (14). Lumican KSPG is a key regulator of collagen fibrillogenesis, a process critical to corneal transparency. Mice lacking lumican show an age-dependent corneal opacity and a high proportion of abnormally thick collagen fibers in the corneal stroma (15).Lumican is also widely present as a non-or low-sulfated glycoprotein in connective tissues of many other organ systems, e.g. skeleton, heart, kidney, and lung (14, 16 -18). During mouse embryonic ocular development, lumican is synthesized by keratocytes; detected as a glycoprotein, not as a KSPG (19); and also transiently expressed by the corneal epithelium, neural retina, and epidermis (14). These observations suggest that epithelial tissues possess the capacity to express lumican under certain conditions. Several studies have demonstrated that SLRP proteins can modulate cellular behaviors, i.e. cell migration and prolifera...
To examine the roles of TGFbeta isoforms on corneal morphogenesis, the eyes of mice that lack TGFbetas were analyzed at different developmental stages for cell proliferation, migration and apoptosis, and for expression patterns of keratin 12, lumican, keratocan and collagen I. Among the three Tgfb(-/-) mice, only Tgfb2(-/-) mice have abnormal ocular morphogenesis characterized by thin corneal stroma, absence of corneal endothelium, fusion of cornea to lens (a Peters'-like anomaly phenotype), and accumulation of hyaline cells in vitreous. In Tgfb2(-/-) mice, fewer keratocytes were found in stroma that has a decreased accumulation of ECM; for example, lumican, keratocan and collagen I were greatly diminished. The absence of TGFbeta2 did not compromise cell proliferation, nor enhance apoptosis. The thinner stroma resulting from decreased ECM synthesis may account for the decreased cell number in the stroma of Tgfb2 null mice. Keratin 12 expression was not altered in Tgfb2(-/-) mice, implicating normal corneal type epithelial differentiation. Delayed appearance of macrophages in ocular tissues was observed in Tgfb2(-/-) mice. Malfunctioning macrophages may account for accumulation of cell mass in vitreous of Tgfb2 null mice.
Lumican is an extracellular matrix glycoprotein widely distributed in mammalian connective tissues. Corneal lumican modified with keratan sulfate constitutes one of the major proteoglycans of the stroma. Lumican-null mice exhibit altered collagen fibril organization and loss of corneal transparency. A closely related protein, keratocan, carries the remaining keratan sulfate of the cornea, but keratocan-null mice exhibit a less severe corneal phenotype. In the current study, we examined the effect of lumican overexpression in corneas of wild type mice. These mice showed no alteration in collagen organization or transparency but had increased keratocan expression at both protein and mRNA levels. Corneas of lumican-null mice showed decreased keratocan. This coupling of keratocan expression with lumican also was observed after intrastromal injection of a lumican expression minigene into the corneal stroma of Lum ؊/؊ mice. Small interfering RNA knockdown of lumican in vitro reduced keratocan expression, whereas co-injection of a lumican-expressing minigene with a -galactosidase reporter driven by the keratocan promoter demonstrated an increase of keratocan transcriptional activity in response to lumican expression in Lum ؊/؊ corneas in vivo. These observations demonstrate that lumican has a novel regulatory role in keratocan expression at the transcriptional level. Such results help provide an explanation for the differences in severity of corneal manifestation found in Lum ؊/؊ and Kera ؊/؊ mice. The results also suggest a critical level of small proteoglycans to be essential for collagen organization but that overabundance is not detrimental to extracellular matrix morphogenesis.
Lumican is one of the major keratan sulfate proteoglycans (KSPG) in vertebrate corneas. We previously cloned the murine lumican cDNA. This study determines the structure of murine lumican gene (Lum) and its expression during mouse embryonic developments. The mouse lumican gene was isolated from a bacterial artificial chromosome mouse genomic DNA library and characterized by polymerase chain reaction and Southern hybridization. The lumican gene spans 6.9 kilobase pairs of mouse genome. The gene consists of three exons and two introns. Exon 1 constitutes 88 bases (b) of untranslated sequence. Exon 2 is 883 b and contains most of the coding sequence of lumican mRNA, and exon 3 has 152 b of coding sequence and 659 b of 3 noncoding sequence. The mouse lumican gene has a TATCA element, a presumptive TATA box, which locates 27 b 5-upstream from the transcription initiation site. Northern hybridization and in situ hybridization indicate that in early stages of embryonic development, day 7 post coitus the embryo expresses little or no lumican. Thereafter, different levels of lumican mRNA can be detected in various organ systems, such as cornea stroma, dermis, cartilage, heart, lung, and kidney. The cornea and heart are the two tissues that have the highest expression in adult. Immunoblotting studies found that KSPG core proteins became abundant in the cornea and sclera by postnatal day 10 but that sulfated KSPG could not be detected until after the eyes open. These results indicate that lumican is widely distributed in most interstitial connective tissues. The modification of lumican with keratan sulfates in cornea is concurrent with eye opening and may contribute to corneal transparency.Corneal strength and transparency depend upon the development and maintenance of an organized extracellular matrix, including uniformly small diameter collagen fibrils with lamellae of consistent interfibrillar spacing. The collagen fibrils of adjacent lamella sheets are perpendicular to one another (1, 2).The mechanism that governs the formation of collagen lamellae in cornea stroma is not well understood. It has been suggested, however, that the ratios of different collagen types in making up the fibrillar corneal collagen and other extracellular specialized matrix components, e.g. proteoglycans and glycoprotein are essential for the development of a transparent cornea (1,(3)(4)(5)(6)(7)(8). In addition to interaction with collagen fibrils, proteoglycans in stroma also play a role in corneal hydration due to their high negative charge of sulfated carbohydrate moieties (9 -11).The hydrophilic properties of the stroma result from stromal proteoglycans that constitute the second most abundant biological materials in stroma, after collagen (12, 13). The keratan sulfate proteoglycans (KSPGs) 1 are uniquely abundant in the cornea, constituting the major proteoglycans of the corneal stroma. Currently, three corneal KSPG core proteins have been identified, i.e. keratocan, lumican, and mimican (osteoglycin), which were previously designated 3...
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