Ocular and Scleral Alterations in Gene-Targeted Lumican-Fibromodulin Double-Null Mice

Chakravarti, Shukti; Paul, Jennifer; Roberts, L.; Chervoneva, Inna; Oldberg, Åke; Birk, David E.

doi:10.1167/iovs.02-0783

Cited by 109 publications

(98 citation statements)

References 39 publications

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“…However, it is inconsistent with corneal transparency. In other tissues, i.e., sclera, tendon, the down regulation of lumican expression was associated with the onset of fibril growth (Ezura et al, 2000;Chakravarti et al, 2003). This is congruent with a key role for lumican-fibril interactions in the regulation of initiation of lateral fibril growth.…”

Section: Discussionmentioning

confidence: 56%

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Collagen fibril assembly during postnatal development and dysfunctional regulation in the lumican‐deficient murine cornea

Chakravarti

Zhang

Chervoneva

et al. 2006

Developmental Dynamics

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The transparent cornea is the outer barrier of the eye and is its major refractive surface. Development of a functional cornea requires a postnatal maturation phase involving development, growth and organization of the stromal extracellular matrix. Lumican, a leucine-rich proteoglycan, is implicated in regulating assembly of collagen fibrils and the highly organized extracellular matrix essential for corneal transparency. We investigated the regulatory role(s) of lumican in fibril assembly during postnatal corneal development using wild type (Lum ϩ/ϩ ) and lumican-null (Lum Ϫ/Ϫ ) mice. In Lum ϩ/ϩ mice, a regular architecture of small-diameter fibrils is achieved in the anterior stroma by postnatal day 10 (P10), while the posterior stroma takes longer to reach this developmental maturity. Thus, the anterior and the posterior stroma follow distinct developmental timelines and may be under different regulatory mechanisms. In Lum Ϫ/Ϫ mice, it is the posterior stroma where abnormal lateral associations of fibrils and thicker fibrils with irregular contours are evident as early as P10. In contrast, the anterior stroma is minimally perturbed by the absence of lumican. In Lum ϩ/ϩ mice, lumican is expressed throughout the developing stroma at P10, with strong expression limited to the posterior stroma in the adult. Therefore, the posterior stroma, which is most vulnerable to lumican-deficiency, demonstrates an early developmental defect in fibril structure and architecture in the Lum Ϫ/Ϫ mouse. These defects underlie the reported increased light scattering and opacity detectable in the adult. Our findings emphasize the early regulation of collagen structure by lumican during postnatal development of the cornea. Developmental Dynamics 235:2493-2506, 2006.

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Section: Discussionmentioning

confidence: 56%

“…However, these leucine-rich proteoglycans may interact with lumican in the regulation of collagen fibrillogenesis. The interactions of the closely related class I versus class II leucine-rich proteoglycans in the regulation of fibrillogenesis have been described (Ezura et al, 2000;Ameye and Young, 2002;Chakravarti et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Collagen fibril assembly during postnatal development and dysfunctional regulation in the lumican‐deficient murine cornea

Chakravarti

Zhang

Chervoneva

et al. 2006

Developmental Dynamics

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“…Moring et al (49) found that biglycan and lumican mRNA levels were lowered in the sclera during experimentally induced myopia and increased during recovery in the tree shrew model. Lum Ϫ/Ϫ mice and Lum Ϫ/Ϫ Fmod Ϫ/Ϫ mice presented altered collagen fibril diameter in sclera (28,29), suggesting that these proteoglycans play an important role in the biomechanical properties of the sclera. Our zebrafish model indicated that the altered collagen fibril diameter in corneal stroma and anterior sclera by zlum knockdown with morpholinos is similar to some features of the Lum Ϫ/Ϫ mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Ϫ/Ϫ mice exhibited elongated axial lengths and thin sclera, which are characteristics of high myopia, and lumicannull mice (Lum Ϫ/Ϫ ) also had a slight elongation of the eyeball (27,28). These findings indicated that these proteoglycans may be directly or indirectly involved in scleral development, resulting in the pathoetiology of high myopia.…”

Section: Fmodmentioning

confidence: 91%

Knockdown of Zebrafish Lumican Gene (zlum) Causes Scleral Thinning and Increased Size of Scleral Coats

Yeh

Liu

Kao

et al. 2010

Journal of Biological Chemistry

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The lumican gene (lum), which encodes one of the major keratan sulfate proteoglycans (KSPGs) in the vertebrate cornea and sclera, has been linked to axial myopia in humans. In this study, we chose zebrafish (Danio rerio) as an animal model to elucidate the role of lumican in the development of axial myopia. The zebrafish lumican gene (zlum) spans ϳ4.6 kb of the zebrafish genome. Like human (hLUM) and mouse (mlum), zlum consists of three exons, two introns, and a TATA box-less promoter at the 5-flanking region of the transcription initiation site. Sequence analysis of the cDNA predicts that zLum encodes 344 amino acids. zLum shares 51% amino acid sequence identity with human lumican. Similar to hLUM and mlum, zlum mRNA is expressed in the eye and many other tissues, such as brain, muscle, and liver as well. Transgenic zebrafish harboring an enhanced GFP reporter gene construct downstream of a 1.7-kb zlum 5-flanking region displayed enhanced GFP expression in the cornea and sclera, as well as throughout the body. Downregulation of zlum expression by antisense zlum morpholinos manifested ocular enlargement resembling axial myopia due to disruption of the collagen fibril arrangement in the sclera and resulted in scleral thinning. Administration of muscarinic receptor antagonists, e.g. atropine and pirenzepine, effectively subdued the ocular enlargement caused by morpholinos in in vivo zebrafish larvae assays. The observation suggests that zebrafish can be used as an in vivo model for screening compounds in treating myopia.Myopia is a very common ocular disorder, which is characterized by excessive elongation of the eyeball. In Taiwan, the prevalence of myopia is about 84% of schoolchildren aged 16 -18, and the prevalence of high myopia (less than Ϫ6.0 D) at 18 years of age is 24% in girls and 18% in boys (1). In contrast, the prevalence of high myopia is much lower in Western countries, about 1% of the general population (2). These studies imply that genetic susceptibility of ethnic differences may account for the high prevalence of myopia in Taiwanese.The sclera contains a collagen-rich extracellular matrix that undergoes significant biochemical and biomechanical remodeling during the development of myopia (3). Linkage studies of high myopia have identified potential loci MYP1 (Xq28) and MYP3 (12q21-23); these loci are within and/or near the loci of the human genome containing several genes that encode small leucine-rich proteoglycans (SLRP), 3 i.e. biglycan (Xq27ter), decorin (12q21-22), lumican (12q21.3-22), and DSPG3 (12q21) (4 -9). Our previous study showed that certain variations (rs3759223 (C3 T)) of single nucleotide polymorphism in the lumican regulatory region may influence the promoter activities of lumican and affect fibrillogenesis in myopic eyes (10). Furthermore, Majava et al. (11) found that a novel single nucleotide polymorphism (c.893-105G3 A) of the lumican gene was associated with high myopia. Recently, our prospective case control study also showed that genetic variation in the regulatory domai...

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“…10). For example, lumican-deficient mice have structurally abnormal corneal fibrils and, as a result, opaque corneas (11)(12)(13). The same is true for decorin-or biglycan-null mice and, to a greater extent, mice with a compound deficiency of decorin and biglycan, suggesting redundant functions of the SLRPs in corneal fibrillogenesis (14,15).…”

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confidence: 94%

Lateral Growth Limitation of Corneal Fibrils and Their Lamellar Stacking Depend on Covalent Collagen Cross-linking by Transglutaminase-2 and Lysyl Oxidases, Respectively

Wang

Uhlig

Eikenberry³

et al. 2014

Journal of Biological Chemistry

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Background: Mechanisms of growth limitation and lamellar stacking of collagen fibrils in cornea remain elusive. Results: Covalent collagen cross-links are formed by catalysis involving both lysyl oxidases and tissue transglutaminase-2. Conclusion: Aldehyde-derived and isopeptide cross-linking of collagen determine lamellar stacking and lateral fibril growth, respectively. Significance: Two types of covalent collagen cross-linking are indispensable for correct corneal morphogenesis.

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Ocular and Scleral Alterations in Gene-Targeted Lumican-Fibromodulin Double-Null Mice

Cited by 109 publications

References 39 publications

Collagen fibril assembly during postnatal development and dysfunctional regulation in the lumican‐deficient murine cornea

Collagen fibril assembly during postnatal development and dysfunctional regulation in the lumican‐deficient murine cornea

Knockdown of Zebrafish Lumican Gene (zlum) Causes Scleral Thinning and Increased Size of Scleral Coats

Lateral Growth Limitation of Corneal Fibrils and Their Lamellar Stacking Depend on Covalent Collagen Cross-linking by Transglutaminase-2 and Lysyl Oxidases, Respectively

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