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

Chakravarti, Shukti; Zhang, Guiyun; Chervoneva, Inna; Roberts, L.; Birk, David E.

doi:10.1002/dvdy.20868

Cited by 71 publications

(76 citation statements)

References 53 publications

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“…33 In our 952delTDcn transgenic mouse model, the structural alterations and functional deficiency are present throughout the corneal stroma but more severe in posterior stroma, which is consistent with the depletion of posterior stroma-restricted lumican. 38 These data suggest that the CSCD phenotype is partially a result of dysregulation of lumican-mediated fibril diameter regulation, and ultrastructural analysis shows structural alterations in the 952delTDcn transgenic mouse model consistent with the lumican-null phenotype (see Supplemental Figure S1 at http://ajp.amjpathol.org). In addition, the overall decrease in decorin and biglycan would be expected to affect the phenotype and may be exacerbated by dominant-negative influences of the mutant decorin influencing fibril as well as cell interactions.…”

Section: Discussionmentioning

confidence: 64%

Pathophysiological Mechanisms of Autosomal Dominant Congenital Stromal Corneal Dystrophy

Chen

Sun

Meng

et al. 2011

The American Journal of Pathology

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Autosomal-dominant congenital stromal corneal dystrophy (CSCD) is a human genetic disease characterized by corneal opacities beginning shortly after birth. It is linked to a frameshift mutation in decorin, resulting in a C-terminal truncation lacking 33 amino acids that includes the "ear" repeat, a feature specific for small leucine-rich proteoglycans. Our goals are to elucidate the roles of the mutant decorin in CSCD pathophysiology and to decipher the mechanism whereby mutant decorin affects matrix assembly. A novel animal model that recapitulates human CSCD was generated. This transgenic mouse model targets expression of truncated decorin to keratocytes, thereby mimicking the human frameshift mutation. Mutant mice expressed both wild-type and mutant decorin. Corneal opacities were found throughout, with increased severity toward the posterior stroma. The architecture of the lamellae was disrupted with relatively normal lamellae separated by regions of abnormal fibril organization. Within abnormal zones, the interfibrillar spacing and the fibril diameters were increased. Truncated decorin negatively affected the expression of endogenous decorin, biglycan, lumican, and keratocan and positively affected fibromodulin. Our results provide a mechanistic explanation for the generation of corneal opacities in CSCD.Thus, truncated decorin acts in a dominant-negative manner to interfere dually with matrix assembly and binding to receptor tyrosine kinases, thereby causing abnormal expression of endogenous small leucinerich proteoglycans leading to structural abnormalities within the cornea and vision loss.

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Section: Discussionmentioning

confidence: 64%

Pathophysiological Mechanisms of Autosomal Dominant Congenital Stromal Corneal Dystrophy

Chen

Sun

Meng

et al. 2011

The American Journal of Pathology

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“…Immunofluorescence Microscopy-Immunolocalization of decorin and biglycan in frozen sections from corneas at different developmental stages was done as previously described (9,15). Anti-mouse decorin antibody was used at 1:200 and antimouse biglycan antiserum at 1:100.…”

Section: Methodsmentioning

confidence: 99%

“…The intermediates undergo linear growth to generate mature fibrils, but no lateral growth. These later steps involve SLRP interactions with stromal collagen fibrils (9,(17)(18)(19). These structural features are essential for corneal transparency.…”

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confidence: 99%

“…Heterotypic interactions involving different fibril-forming collagens regulate fibril nucleation during development (1,6). In contrast, interactions involving fibrils and small leucine-rich proteoglycans (SLRPs) 2 are implicated in the regulation of linear and lateral growth of mature fibrils from preformed intermediates (5,(7)(8)(9)(10). The focus of this work is to elucidate the differential regulatory role(s) of decorin and biglycan in fibrillogenesis.…”

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confidence: 99%

“…To date, only lumican-null mice have been shown to have structural defects in corneal fibrils. This involves a spatially restricted loss of lateral growth regulation in the posterior stroma (8,9,25,26). An interaction between lumican and keratocan with lumican regulating keratocan expression has been documented (16).…”

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confidence: 99%

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Genetic Evidence for the Coordinated Regulation of Collagen Fibrillogenesis in the Cornea by Decorin and Biglycan

Zhang

Chen

Goldoni

et al. 2009

Journal of Biological Chemistry

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188

177

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Decorin and biglycan are class I small leucine-rich proteoglycans (SLRPs) involved in regulation of collagen fibril and matrix assembly. We hypothesize that tissue-specific matrix assembly, such as in the cornea, requires a coordinate regulation involving multiple SLRPs. To this end, we investigated the expression of decorin and biglycan in the cornea of mice deficient in either SLRP gene and in double-mutant mice. Decorin and biglycan exhibited overlapping spatial expression patterns throughout the corneal stroma with differential temporal expression. Whereas decorin was expressed at relatively high levels in all developmental stages, biglycan expression was high early, decreased during development, and was present at very low levels in the mature cornea. Ultrastructural analyses demonstrated comparable fibril structure in the decorin-and biglycan-null corneas compared with wild-type controls. We found a compensatory up-regulation of biglycan gene expression in the decorindeficient mice, but not the reverse. Notably, the corneas of compound decorin/biglycan-null mice showed severe disruption in fibril structure and organization, especially affecting the posterior corneal regions, corroborating the idea that biglycan compensates for the loss of decorin. Fibrillogenesis assays using recombinant decorin and biglycan confirmed a functional compensation, with both having similar effects at high SLRP/collagen ratios. However, at low ratios decorin was a more efficient regulator. The use of proteoglycan or protein core yielded comparable results. These findings provide firm genetic evidence for an interaction of decorin and biglycan during corneal development and further suggest that decorin has a primary role in regulating fibril assembly, a function that can be fine-tuned by biglycan during early development.The characteristic architecture of different connective tissues is established through tissue-specific regulation of collagen fibrillogenesis and matrix assembly. Multiple steps are involved in collagen fibrillogenesis, including the nucleation of collagen assembly, assembly of immature fibril intermediates, and linear and lateral fibril growth of preformed intermediates (1-5). Each step is independently regulated through interactions of extracellular macromolecules with fibrils. Heterotypic interactions involving different fibril-forming collagens regulate fibril nucleation during development (1, 6). In contrast, interactions involving fibrils and small leucine-rich proteoglycans (SLRPs) 2 are implicated in the regulation of linear and lateral growth of mature fibrils from preformed intermediates (5, 7-10). The focus of this work is to elucidate the differential regulatory role(s) of decorin and biglycan in fibrillogenesis.SLRPs compose a family of five classes of structurally related, but genetically distinct molecules. The members within each class exhibit high protein homology and primary structure identity (11). Decorin and biglycan are class I SLRPs; and fibromodulin, keratocan, and lumican are class II ...

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Development of the corneal stroma, and the collagen–proteoglycan associations that help define its structure and function

Quantock

Young

2008

Developmental Dynamics

110

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The cornea of the eye is a unique, transparent connective tissue. It is comprised predominantly of collagen fibrils, remarkably uniform in diameter and regularly spaced, organized into an intricate lamellar array. Its establishment involves a precisely controlled sequence of developmental events in which the embryonic cornea undergoes major structural transformations that ultimately determine tissue form and function. In this article, we will review corneal developmental dynamics from a structural perspective, consider the roles and interrelationships of collagens and proteoglycans, and comment on contemporary concepts and current challenges pertinent to developmental processes that result in an optically clear, mature cornea.

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

Cited by 71 publications

References 53 publications

Pathophysiological Mechanisms of Autosomal Dominant Congenital Stromal Corneal Dystrophy

Pathophysiological Mechanisms of Autosomal Dominant Congenital Stromal Corneal Dystrophy

Genetic Evidence for the Coordinated Regulation of Collagen Fibrillogenesis in the Cornea by Decorin and Biglycan

Development of the corneal stroma, and the collagen–proteoglycan associations that help define its structure and function

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