Structural Abnormalities of the Cornea and Lid Resulting from Collagen V Mutations

Segev, Fani; Hèon, Elise; Cole, William G.; Wenstrup, Richard J.; Young, Felix; Slomovic, Allan R.; Rootman, David S.; Whitaker‐Menezes, Diana; Chervoneva, Inna; Birk, David E.

doi:10.1167/iovs.05-0771

Cited by 105 publications

(83 citation statements)

References 45 publications

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“…In addition, the initiation of fibril assembly does not appear to involve lumican since our data demonstrated no structural changes until after eye opening. This early step has been shown to be regulated by type I/V collagen interactions (Wenstrup et al, 2004;Segev et al, 2006). The absence of interactions between lumican and the fibrils lead to a dysfunctional regulation of fibrillogenesis, particularly in the posterior stroma.…”

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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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: 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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“…Further, there is increased expression of type XIII collagen in the myofibroblasts of stromal scar tissue in keratoconus corneas, indicating a role in wound healing (Maatta et al 2006) (Table 1). (Segev et al 2006;Sun et al 2011) Collagen, type VIII, alpha 1 and alpha 2…”

Section: Constituents Of Corneal Stromal Ecmmentioning

confidence: 99%

The integrin needle in the stromal haystack: emerging role in corneal physiology and pathology

Parapuram

Hodge

2014

J. Cell Commun. Signal.

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Several studies have established the role of activated corneal keratocytes in the fibrosis of the cornea. However, the role of keratocytes in maintaining the structural integrity of a normal cornea is less appreciated. We focus on the probable functions of integrins in the eye and of the importance of integrin-mediated keratocyte interactions with stromal matrix in the maintenance of corneal integrity. We point out that further understanding of how keratocytes interact with their matrix could establish a novel direction in preventing corneal pathology including loss of structural integrity as in keratoconus or as in fibrosis of the corneal stroma.Keywords Cornea . Keratocytes . Corneal stroma . Extracellular matrix . Integrins . KeratoconusThe simple cellular organization of the cornea is belied by its fascinating specialization for transparency. The cornea has three main tissue layers, the outer epithelium, the stroma in the middle and the inner endothelial layer. The stromal connective tissue, the layer mainly responsible for the corneal configuration, constituting nearly 80 % of the thickness of the cornea, is extremely resilient, capable of resisting intraocular pressure and protecting the posterior structures of the eye. The stromal tissue consists of lamellae of orthogonally arranged collagen fibrils surrounded by proteoglycans; in between the lamellae of collagen are found the keratocytes. The nearorderly arrangement of collagen lamellae, the narrow diameter of the collagen fibrils, regular interfibrillar space, associated proteoglycans and the expression of crystalline proteins in the keratocytes (Birk 2001;Kao and Liu 2002;Jester et al. 2007; Hassell and Birk 2010) are some of the main factors responsible for corneal transparency. Consequently, the factors affecting corneal transparency such as fibrotic changes due to disease or injury are problems primarily associated with the stroma. Thus it is important to achieve further understanding of the mechanisms by which the stroma acquires and maintains its structural integrity and its transparency.

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“…Type V collagen, a component of heterotypic type I/V fibrils in cornea (10), has been shown to contribute to the production of small-diameter fibrils, with its retained α1(V) N-propeptide domain implicated as modulator (11,12). In vivo as well, evidence from studies of gene knockout mice suggests that type V collagen is a potent modulator of corneal fibril diameter (13,14), although coordinated interaction between this and other factors potentially indicates a more complex regulatory control in the tissue microenvironment.Mechanisms governing the deposition of tissue-specific, suprafibrillar architectures by cells in different tissues are even less well-understood than those controlling individual fibril formation. Developing tendon has been the most widely studied tissue in this regard (15)(16)(17)(18)(19)(20).…”

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confidence: 99%

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Three-dimensional aspects of matrix assembly by cells in the developing cornea

Young

Knupp

Pinali

et al. 2014

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

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Cell-directed deposition of aligned collagen fibrils during corneal embryogenesis is poorly understood, despite the fact that it is the basis for the formation of a corneal stroma that must be transparent to visible light and biomechanically stable. Previous studies of the structural development of the specialized matrix in the cornea have been restricted to examinations of tissue sections by conventional light or electron microscopy. Here, we use volume scanning electron microscopy, with sequential removal of ultrathin surface tissue sections achieved either by ablation with a focused ion beam or by serial block face diamond knife microtomy, to examine the microanatomy of the cornea in three dimensions and in large tissue volumes. The results show that corneal keratocytes occupy a significantly greater tissue volume than was previously thought, and there is a clear orthogonality in cell and matrix organization, quantifiable by Fourier analysis. Three-dimensional reconstructions reveal actin-associated tubular cell protrusions, reminiscent of filopodia, but extending more than 30 μm into the extracellular space. The highly extended network of these membrane-bound structures mirrors the alignment of collagen bundles and emergent lamellae and, we propose, plays a fundamental role in dictating the orientation of collagen in the developing cornea.C onnective tissues fulfill diverse functions but conform to a general structural plan of cells surrounded by an extracellular matrix in which collagen is the main structural element (1, 2). Composition and tissue-specific organization of the component collagen fibrils are considered to be critically important for the functional properties of any particular tissue. The unique transparent quality of the cornea arises from its remarkably ordered architecture of aligned and regularly spaced fibrils with a small, consistent diameter (∼30 nm), which are arranged, not into fibers or fascicles as in most other tissues but in superimposed, flattened layers, or lamellae. Lamellae and their component collagen fibrils exhibit preferential orientations throughout the corneal thickness (3), which appear to be closely related to the biomechanical loads to which the tissue is subjected. In adult vertebrates, lamellae traverse the full diameter of the cornea for most of its thickness, and in the avian eye-the subject of most developmental studies-undergo a gradual rotation in their orientation with depth (4). Individual collagen fibrils within midstromal lamellae also appear to traverse the entire diameter of the cornea, a distance of ∼11 mm in adult human eyes. The extraordinary level of order in matrix organization within a hierarchy of fibril, lamella, and stroma overall appears to reflect a considerable level of regulatory influence presumably involving both cell activity and intermolecular interactions.Collagen fibrils exhibit a microfibrillar substructure (5-7), undergoing self-assembly spontaneously in vitro from soluble monomeric collagen in a process largely dependent upon the phy...

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Structural Abnormalities of the Cornea and Lid Resulting from Collagen V Mutations

Cited by 105 publications

References 45 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

The integrin needle in the stromal haystack: emerging role in corneal physiology and pathology

Three-dimensional aspects of matrix assembly by cells in the developing cornea

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